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Tian J, Xie Y, Ye S, Hu Y, Feng J, Li Y, Lou Z, Ruan L, Wang Z. S-ketamine ameliorates post-stroke depression in mice via attenuation of neuroinflammation, synaptic restoration, and BDNF pathway activation. Biochem Biophys Res Commun 2025; 769:151965. [PMID: 40367907 DOI: 10.1016/j.bbrc.2025.151965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/17/2025] [Accepted: 05/06/2025] [Indexed: 05/16/2025]
Abstract
The available therapeutic options for post-stroke depression patients are limited. Although SSRIs are the most commonly prescribed antidepressants, their slow onset of action and the higher risk of adverse effects or contraindications have led to an urgent need to develop fast-acting and highly specific antidepressants tailored to the needs of PSD patients. Therefore, ketamine has drawn attention. While ketamine has been shown to exert rapid antidepressant effects in numerous studies, whether it can ameliorate PSD remains unclear, and the molecular and cellular mechanisms underlying its therapeutic action in PSD are largely elusive. In this study, we used a PSD preclinical model induced by photothrombosis and chronic restraint stress to investigate the effects of S-ketamine. The present study demonstrates that a single acute intraperitoneal injection of 10 mg/kg S-ketamine on the first day after PSD significantly alleviates depressive-like behaviours in PSD mice. In addition, this improvement was maintained for at least five consecutive days. Mechanistically, S-ketamine reduced pro-inflammatory cytokines in the medial prefrontal cortex (mPFC), mitigated synaptic damage (evidenced by increased dendritic spine density, SYP, and PSD-95 expression). Furthermore, S-ketamine treatment upregulated the expression of brain-derived neurotrophic factor (BDNF), tropomyosin related kinase B (TrkB), phosphorylated serine/threonine-specific protein kinase B (p-Akt), phosphorylated extracellular signal-regulated kinase (p-Erk), phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII), and phosphorylated cAMP response element binding protein (p-CREB). Overall, S-ketamine shows promise for PSD treatment through its anti-inflammatory, synaptic enhancing, and BDNF pathway modulating effects. This research enhances our understanding of the pathological mechanisms underlying PSD and provides new therapeutic insights for its treatment.
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Affiliation(s)
- Jiaxin Tian
- Department of Psychosomatic Medicine, the First Affiliated Hospital of Ningbo University, Zhejiang Regional Medical Center, Ningbo, Zhejiang, 315010, PR China; School of Pharmacy, Basic Medical Sciences, Health Science Center, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, PR China
| | - Yanhong Xie
- School of Pharmacy, Basic Medical Sciences, Health Science Center, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, PR China
| | - Sen Ye
- School of Pharmacy, Basic Medical Sciences, Health Science Center, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, PR China
| | - Yongfeng Hu
- School of Pharmacy, Basic Medical Sciences, Health Science Center, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, PR China
| | - Jiaxin Feng
- School of Pharmacy, Basic Medical Sciences, Health Science Center, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, PR China
| | - Yi Li
- School of Pharmacy, Basic Medical Sciences, Health Science Center, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, PR China
| | - Zhongze Lou
- Department of Psychosomatic Medicine, the First Affiliated Hospital of Ningbo University, Zhejiang Regional Medical Center, Ningbo, Zhejiang, 315010, PR China
| | - Liemin Ruan
- Department of Psychosomatic Medicine, the First Affiliated Hospital of Ningbo University, Zhejiang Regional Medical Center, Ningbo, Zhejiang, 315010, PR China.
| | - Zhengchun Wang
- School of Pharmacy, Basic Medical Sciences, Health Science Center, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, PR China.
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Kwon H, Jeon J, Cho E, Moon S, Park AY, Kwon HJ, Kwon KJ, Ryu JH, Shin CY, Yi JH, Kim DH. Chronic stress-related behavioral and synaptic changes require caspase-3 activation in the ventral hippocampus of male mice. Neuropharmacology 2025; 272:110431. [PMID: 40147637 DOI: 10.1016/j.neuropharm.2025.110431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/26/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Although numerous studies have suggested that chronic stress is a major risk factor for major depressive disorder, the process by which stress causes depression is still not fully understood. Previously, we investigated glucocorticoids, which are stress response hormones that activate a synapse-weakening pathway. Therefore, we hypothesized that chronic stress may cause synaptic depression, which could reduce excitability related to emotions. Animals underwent chronic restraint stress (CRS), followed by basal synaptic transmission measurement in hippocampal slices to assess synaptic function. Drugs were infused into the ventral hippocampus via cannulation before behavioral tests, including forced swimming, tail suspension, and sucrose intake tests, which evaluated depressive-like behaviors and anhedonia. The field excitatory postsynaptic potentials (fEPSPs) are reduced by chronic restraint stress (CRS) in the ventral hippocampus. The ventral hippocampi of mice treated with CRS showed low levels of fEPSP after the forced swim test (FST). In the FST and tail suspension test, CRS-induced increases in immobility time were prevented by the acute inhibition of AMPAR internalization by Tat-GluA23y, which also prevented fEPSP reduction. Mice lacking caspase-3 exhibited resilience to CRS-induced increases in immobility time in the FST, as well as changes in the functionality of synaptic AMPAR. Finally, the caspase-3 inhibitor Z-DEVD-FMK rapidly blocked the CRS-induced increase in immobility time in the FST and the CRS-induced decrease in sucrose preference. These findings suggest that chronic stress-related behavioral changes may require caspase-3-dependent alterations in ventral hippocampal synapses.
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Affiliation(s)
- Huiyoung Kwon
- Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, Republic of Korea
| | - Jieun Jeon
- Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul, 05029, Republic of Korea
| | - Eunbi Cho
- Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul, 05029, Republic of Korea
| | - Somin Moon
- Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul, 05029, Republic of Korea
| | - A Young Park
- Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul, 05029, Republic of Korea
| | - Hyun Ji Kwon
- Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul, 05029, Republic of Korea
| | - Kyoung Ja Kwon
- Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul, 05029, Republic of Korea; Institute of Biomedical Science & Technology, Konkuk University, Seoul, 05029, Republic of Korea
| | - Jong Hoon Ryu
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Chan Young Shin
- Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul, 05029, Republic of Korea; Institute of Biomedical Science & Technology, Konkuk University, Seoul, 05029, Republic of Korea
| | - Jee Hyun Yi
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, 34141, Republic of Korea.
| | - Dong Hyun Kim
- Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul, 05029, Republic of Korea; Institute of Biomedical Science & Technology, Konkuk University, Seoul, 05029, Republic of Korea.
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Wellington NJ, Boųcas AP, Lagopoulos J, Quigley BL, Kuballa AV. Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD. Psychopharmacology (Berl) 2025; 242:1197-1243. [PMID: 40097854 DOI: 10.1007/s00213-025-06756-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 02/03/2025] [Indexed: 03/19/2025]
Abstract
RATIONALE Existing studies predominantly focus on the molecular and neurobiological mechanisms underlying Ketamine's acute treatment effects on post-traumatic stress disorder (PTSD). This emphasis has largely overlooked its sustained therapeutic effects, which hold significant potential for the development of targeted interventions. OBJECTIVES This systematic review examines the pharmacokinetic and pharmacodynamic effects of ketamine on PTSD, differentiating between immediate and sustained molecular effects. METHOD A comprehensive search across databases (Web of Science, Scopus, Global Health, PubMed) and grey literature yielded 317 articles, where 29 studies met the inclusion criteria. These studies included preclinical models and clinical trials, through neurotransmitter regulation, gene expression, synaptic plasticity, and neural pathways (PROSPERO ID: CRD42024582874). RESULTS We found accumulating evidence that the immediate effects of ketamine, which involve changes in GABA, glutamate, and glutamine levels, trigger the re-regulation of BDNF, enhancing synaptic plasticity via pathways such as TrkB and PSD-95. Other molecular influences also include c-Fos, GSK-3, HDAC, HCN1, and the modulation of hormones like CHR and ACTH, alongside immune responses (IL-6, IL-1β, TNF-α). Sustained effects arise from neurotransmitter remodulations and involve prolonged changes in gene expression. These include mTOR-mediated BDNF expression, alterations in GSK-3β, FkBP5, GFAP, ERK phosphorylation, and epigenetic modifications (DNMT3, MeCP2, H3K27me3, mir-132, mir-206, HDAC). CONCLUSION These molecular changes promote long-term synaptic stability and re-regulation in key brain regions, contributing to prolonged therapeutic benefits. Understanding the sustained molecular and epigenetic mechanisms behind ketamine's effects is critical for developing safe and effective personalised treatments, potentially leading to more effective recovery.
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Affiliation(s)
- Nathan J Wellington
- National PTSD Research Centre, Thompson Institute, University of the Sunshine Coast (UniSC), Birtinya, QLD, Australia.
- School of Health, UniSC, Sippy Downs, QLD, Australia.
- Centre for Bioinnovation, UniSC, Sippy Downs, QLD, Australia.
- Sunshine Coast Hospital and Health Service, Sunshine Coast Health Institute, Birtinya, QLD, Australia.
| | - Ana P Boųcas
- National PTSD Research Centre, Thompson Institute, University of the Sunshine Coast (UniSC), Birtinya, QLD, Australia
| | - Jim Lagopoulos
- Thompson Brain and Mind Healthcare, Maroochydore, QLD, Australia
| | - Bonnie L Quigley
- National PTSD Research Centre, Thompson Institute, University of the Sunshine Coast (UniSC), Birtinya, QLD, Australia
- Centre for Bioinnovation, UniSC, Sippy Downs, QLD, Australia
- Sunshine Coast Hospital and Health Service, Sunshine Coast Health Institute, Birtinya, QLD, Australia
| | - Anna V Kuballa
- School of Health, UniSC, Sippy Downs, QLD, Australia
- Centre for Bioinnovation, UniSC, Sippy Downs, QLD, Australia
- Sunshine Coast Hospital and Health Service, Sunshine Coast Health Institute, Birtinya, QLD, Australia
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Lucantonio F, Roeglin J, Li S, Lu J, Shi A, Czerpaniak K, Fiocchi FR, Bontempi L, Shields BC, Zarate CA, Tadross MR, Pignatelli M. Ketamine rescues anhedonia by cell-type- and input-specific adaptations in the nucleus accumbens. Neuron 2025; 113:1398-1412.e4. [PMID: 40112815 PMCID: PMC12064382 DOI: 10.1016/j.neuron.2025.02.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 01/09/2025] [Accepted: 02/20/2025] [Indexed: 03/22/2025]
Abstract
Ketamine is recognized as a rapid and sustained antidepressant, particularly for major depression unresponsive to conventional treatments. Anhedonia is a common symptom of depression for which ketamine is highly efficacious, but the underlying circuits and synaptic changes are not well understood. Here, we show that the nucleus accumbens (NAc) is essential for ketamine's effect in rescuing anhedonia in mice subjected to chronic stress. Specifically, a single exposure to ketamine rescues stress-induced decreased strength of excitatory synapses on NAc-D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs). Using a cell-specific pharmacology method, we establish the necessity of this synaptic restoration for the sustained therapeutic effects of ketamine on anhedonia. Examining causal sufficiency, artificially increasing excitatory synaptic strength onto D1-MSNs recapitulates the behavioral amelioration induced by ketamine. Finally, we used opto- and chemogenetic approaches to determine the presynaptic origin of the relevant synapses, implicating monosynaptic inputs from the medial prefrontal cortex and ventral hippocampus.
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Affiliation(s)
- Federica Lucantonio
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
| | - Jacob Roeglin
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
| | - Shuwen Li
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
| | - Jaden Lu
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
| | - Aleesha Shi
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
| | - Katherine Czerpaniak
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
| | - Francesca R Fiocchi
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
| | | | - Brenda C Shields
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Carlos A Zarate
- Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
| | - Michael R Tadross
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Marco Pignatelli
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
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Costa BM, Hines D, Phillip N, Boehringer SC, Anandakrishnan R, Council-Troche M, Davis JL. Preliminary pharmacokinetics and in vivo studies indicate analgesic and stress mitigation effects of a novel NMDA receptor modulator. J Pharmacol Exp Ther 2025; 392:103401. [PMID: 40086100 DOI: 10.1016/j.jpet.2025.103401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/21/2025] [Accepted: 02/05/2025] [Indexed: 03/16/2025] Open
Abstract
N-methyl D-aspartate receptor (NMDAR) channel blockers produce analgesic and antidepressant effects by preferentially inhibiting the GluN2D subtype at lower doses. Given the distinct physiological role of GluN2 subunits, we hypothesized that compounds capable of simultaneously modulating GluN2A and GluN2D subtypes in opposite directions could serve as effective analgesics with minimal cognitive adverse effects. In this translational study, we investigated the in vivo effects of costa NMDAR stimulator 4 (CNS4), a recently discovered glutamate concentration-dependent NMDAR modulator. Pharmacokinetic data revealed that CNS4 reaches peak plasma and brain concentrations within 0.25 hours after intraperitoneal injection, with brain concentrations reaching values up to 8.4% of those in plasma (64.9 vs 5.47 μg/mL). Preliminary results showed that CNS4, a nonopioid compound, increased escape latency in mice during a hotplate assay by 1.74-fold compared with saline. In a fear conditioning experiment, CNS4 anecdotally reduced the electric shock sensation and significantly decreased stress-related defecation (fecal pellets: males, 21 vs 1; females, 19 vs 3). CNS4 also improved hyperarousal behavior (25 vs 4 jumps), without affecting fear memory parameters such as freezing episodes, duration, or latency. CNS4 caused no changes in locomotion across 8 of 9 parameters studied. Remarkably, approximately 50 hours after fear conditioning training, CNS4 prevented stress-induced excessive sucrose drinking behavior by more than 2-fold both in male and female mice. These findings suggest that CNS4 penetrates brain tissue and produces pharmacological effects such as those of NMDAR-targeting drugs but with a distinct mechanism, avoiding the undesirable side effects typical of traditional NMDAR blockers. Therefore, CNS4 holds potential as a novel nonopioid analgesic, warranting further investigation. SIGNIFICANCE STATEMENT: N-methyl D-aspartate (NMDA)-subtype glutamate receptors are an attractive target for chronic pain and posttraumatic stress disorder treatments because they play a critical role in forming emotional memories of stressful events. In this translational pharmacology work, we demonstrate the central analgesic and stress-mitigating characteristics of a novel glutamate concentration-biased NMDA receptor modulator, costa NMDA receptor stimulator 4.
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Affiliation(s)
- Blaise M Costa
- Pharmacology Division, Edward Via Virginia College of Osteopathic Medicine, Blacksburg, Virginia; Center for One Health Research, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia.
| | - De'Yana Hines
- Department of Biomedical Engineering and Mechanics, Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Blacksburg, Virginia
| | - Nakia Phillip
- Pharmacology Division, Edward Via Virginia College of Osteopathic Medicine, Blacksburg, Virginia
| | - Seth C Boehringer
- Pharmacology Division, Edward Via Virginia College of Osteopathic Medicine, Blacksburg, Virginia; Department of Biochemistry, Virginia Tech, Blacksburg, Virginia
| | - Ramu Anandakrishnan
- Pharmacology Division, Edward Via Virginia College of Osteopathic Medicine, Blacksburg, Virginia; Center for One Health Research, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia
| | - McAlister Council-Troche
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia
| | - Jennifer L Davis
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia
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Su TP, Cheng LK, Tu PC, Chen LF, Lin WC, Li CT, Bai YM, Tsai SJ, Chen MH. Low-dose ketamine improved brain network integrity among patients with treatment-resistant depression and suicidal ideation. Psychiatry Res 2025; 345:116377. [PMID: 39889566 DOI: 10.1016/j.psychres.2025.116377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/20/2025] [Accepted: 01/25/2025] [Indexed: 02/03/2025]
Abstract
BACKGROUND Ketamine is a dissociative drug used for the treatment of depression. However, the neurofunctional mechanism underlying the antidepressant effect of ketamine remains unknown. According to previous research, low-dose ketamine affects large-scale brain networks, including default-mode and salient networks. METHODS A total of 43 patients with treatment-resistant depression (TRD) and suicidal ideation (SI) were randomly assigned to receive a single infusion of either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. Depressive and suicidal symptoms were evaluated using the 17-item Hamilton Depression Rating Scale and the Columbia-Suicide Severity Rating Scale: Ideation Severity Subscale. Resting-state functional magnetic resonance imaging was performed at baseline and on day 3 after infusion. Graph theoretic metrics such as degree centrality and clustering coefficient were examined. RESULTS Relative to midazolam use, low-dose ketamine infusion reduced depressive (p = 0.001) and suicidal (p = 0.025) symptoms and improved the brain network integrity, including increased degree centrality and clustering coefficient in the angular gyrus and increased degree centrality in the right thalamus. DISCUSSION Neurofunctional changes in the thalamus and default-mode network (angular gyrus) may be associated with the antidepressant effect of ketamine on patients with TRD and SI. CLINICAL TRIALS REGISTRATION UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000033916.
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Affiliation(s)
- Tung-Ping Su
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Psychiatry, General Cheng Hsin Hospital, Taipei, Taiwan
| | - Li-Kai Cheng
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Pei-Chi Tu
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Philosophy of Mind and Cognition, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Li-Fen Chen
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan; Brain Research Centre, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Chen Lin
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Cheng-Ta Li
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ya-Mei Bai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shih-Jen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Mu-Hong Chen
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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Ponce-Regalado MD, Becerril-Villanueva E, Maldonado-García JL, Moreno-Lafont MC, Martínez-Ramírez G, Jacinto-Gutiérrez S, Arreola R, Sánchez-Huerta K, Contis-Montes de Oca A, López-Martínez KM, Bautista-Rodríguez E, Chin-Chan JM, Pavón L, Pérez-Sánchez G. Comprehensive view of suicide: A neuro-immune-endocrine approach. World J Psychiatry 2025; 15:98484. [PMID: 39974471 PMCID: PMC11758041 DOI: 10.5498/wjp.v15.i2.98484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 11/26/2024] [Accepted: 12/23/2024] [Indexed: 01/14/2025] Open
Abstract
Suicide is defined as the act of a person attempting to take their own life by causing death. Suicide is a complex phenomenon that is influenced by a multitude of factors, including psychosocial, cultural, and religious aspects, as well as genetic, biochemical, and environmental factors. From a biochemical perspective, it is crucial to consider the communication between the endocrine, immune, and nervous systems when studying the etiology of suicide. Several pathologies involve the bidirectional communication between the peripheral activity and the central nervous system by the action of molecules such as cytokines, hormones, and neurotransmitters. These humoral signals, when present in optimal quantities, are responsible for maintaining physiological homeostasis, including mood states. Stress elevates the cortisol and proinflammatory cytokines levels and alter neurotransmitters balance, thereby increasing the risk of developing a psychiatric disorder and subsequently the risk of suicidal behavior. This review provides an integrative perspective about the neurochemical, immunological, and endocrinological disturbances associated with suicidal behavior, with a particular focus on those alterations that may serve as potential risk markers and/or indicators of the state preceding such a tragic act.
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Affiliation(s)
- María D Ponce-Regalado
- Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitlán de Morelos 47620, Jalisco, Mexico
| | - Enrique Becerril-Villanueva
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
| | - José Luis Maldonado-García
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México 04510, Mexico
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 11350, Mexico
| | - Martha C Moreno-Lafont
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 11350, Mexico
| | - Gabriela Martínez-Ramírez
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
- Facultad de Medicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional autónoma de México, Tlalnepantla 54090, Mexico
| | - Salomón Jacinto-Gutiérrez
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
| | - Rodrigo Arreola
- Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
| | - Karla Sánchez-Huerta
- Laboratorio de Neurociencias, Subdirección de Medicina Experimental, Instituto Nacional de Pediatría, Ciudad de México 04530, Mexico
| | - Arturo Contis-Montes de Oca
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | | | | | - José Miguel Chin-Chan
- Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Campeche, Campeche 24039, Mexico
| | - Lenin Pavón
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
| | - Gilberto Pérez-Sánchez
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 11340, Mexico
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Zimbelman AR, Wong B, Murray CH, Wolf ME, Stefanik MT. Dopamine D1 and NMDA Receptor Co-Regulation of Protein Translation in Cultured Nucleus Accumbens Neurons. Neurochem Res 2024; 50:27. [PMID: 39567459 PMCID: PMC11888153 DOI: 10.1007/s11064-024-04283-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/22/2024]
Abstract
Protein translation is essential for some forms of synaptic plasticity. Here we used fluorescent noncanonical amino acid tagging (FUNCAT) to examine whether dopamine modulates protein translation in cultured nucleus accumbens (NAc) medium spiny neurons (MSN). These neurons were co-cultured with cortical neurons to restore excitatory synapses. We measured translation in MSNs under basal conditions and after disinhibiting excitatory transmission using the GABAA receptor antagonist bicuculline (2 h). Under basal conditions, translation was not altered by the D1-class receptor (D1R) agonist SKF81297 or the D2-class receptor (D2R) agonist quinpirole. Bicuculline alone robustly increased translation. This was reversed by quinpirole but not SKF81297. It was also reversed by co-incubation with the D1R antagonist SCH23390, but not the D2R antagonist eticlopride, suggesting dopaminergic tone at D1Rs. This was surprising because no dopamine neurons are present. An alternative explanation is that bicuculline activates translation by increasing glutamate tone at NMDA receptors (NMDAR) within D1R/NMDAR heteromers. Supporting this, immunocytochemistry and proximity ligation assays revealed D1R/NMDAR heteromers on NAc cells both in vitro and in vivo, confirming previous results. Furthermore, bicuculline's effect was reversed to the same extent by SCH23390 alone, the NMDAR antagonist APV alone, or SCH23390 + APV. These results suggest that: (1) excitatory transmission stimulates translation in NAc MSNs, (2) this is opposed when glutamate activates D1R/NMDAR heteromers, even in the absence of dopamine, and (3) antagonist occupation of D1Rs within the heteromers prevents their activation. Our study is the first to suggest a role for D2 receptors and D1R/NMDAR heteromers in regulating protein translation.
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Affiliation(s)
- Alexa R Zimbelman
- Department of Psychology and Neuroscience, North Central College, 30 N. Brainard St., Naperville, IL, 60540, USA
| | - Benjamin Wong
- Department of Psychology and Neuroscience, North Central College, 30 N. Brainard St., Naperville, IL, 60540, USA
| | - Conor H Murray
- Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
- Present Address: UCLA Center for Cannabis and Cannabinoids, Semel Institute for Neuroscience & Human Behavior, Los Angeles, CA, 90025, USA
| | - Marina E Wolf
- Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
- Present Address: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97212, USA
| | - Michael T Stefanik
- Department of Psychology and Neuroscience, North Central College, 30 N. Brainard St., Naperville, IL, 60540, USA.
- Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA.
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9
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Kavalali ET, Monteggia LM. Synaptic basis of rapid antidepressant action. Eur Arch Psychiatry Clin Neurosci 2024:10.1007/s00406-024-01898-6. [PMID: 39343821 DOI: 10.1007/s00406-024-01898-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 09/07/2024] [Indexed: 10/01/2024]
Abstract
The discovery of ketamine's rapid antidepressant action has generated intense interest in the field of neuropsychiatry. This discovery demonstrated that to alleviate the symptoms of depression, treatments do not need to elicit substantive alterations in neuronal circuitry or trigger neurogenesis, but rather drive synaptic plasticity mechanisms to compensate for the underlying pathophysiology. The possibility of a rapidly induced antidepressant effect makes therapeutic pursuit of fast-acting neuropsychiatric medications against mood disorders plausible. In the meantime, the accumulating clinical as well as preclinical observations raise critical questions on the nature of the specific synaptic plasticity events that mediate these rapid antidepressant effects. This work has triggered the current growing interest in alternative psychoactive compounds that are thought to have similar properties to ketamine and its action. This review covers our insight into these questions based on the work our group has conducted on this topic in the last decade.
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Affiliation(s)
- Ege T Kavalali
- Department of Pharmacology and the Vanderbilt Brain Institute, Vanderbilt University, 465 21st Avenue South, Suite 7130 Medical Building III, Nashville, TN, 37240-7933, USA.
- Department of Pharmacology and the Vanderbilt Brain Institute, Vanderbilt University, 465 21st Avenue South, Suite 7130 Medical Building III, Nashville, TN, 37240-7933, USA.
| | - Lisa M Monteggia
- Department of Pharmacology and the Vanderbilt Brain Institute, Vanderbilt University, 465 21st Avenue South, Suite 7130 Medical Building III, Nashville, TN, 37240-7933, USA.
- Department of Pharmacology and the Vanderbilt Brain Institute, Vanderbilt University, 465 21st Avenue South, Suite 7130 Medical Building III, Nashville, TN, 37240-7933, USA.
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10
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Khalifian C, Rashkovsky K, Mitchell E, Bismark A, Wagner AC, Knopp KC. A novel framework for ketamine-assisted couple therapy. Front Psychiatry 2024; 15:1376646. [PMID: 39193577 PMCID: PMC11347343 DOI: 10.3389/fpsyt.2024.1376646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 07/17/2024] [Indexed: 08/29/2024] Open
Abstract
Intimate relationship distress is prevalent and is associated with poorer health, mental health, and mortality outcomes. Evidence-based couple therapies target cognitive, behavioral, and emotional processes that underlie relationship dysfunction. Increasing research and clinical evidence supports the efficacy of ketamine-assisted psychotherapy (KAP) for addressing clinical mental health concerns, including depression, anxiety disorders, posttraumatic stress disorder, and more. The purported mechanisms of KAP are also likely to improve psychosocial and relational functioning for patients and may be useful for supporting change mechanisms in couple therapy. This paper reviews the current evidence for therapeutic ketamine and KAP and outlines how the mechanisms of ketamine therapy may also augment the cognitive, behavioral, and emotional interventions in the most commonly used evidence-based couple therapies. Key mechanisms include increased neuroplasticity, changes in functional connectivity, adaptive dissociation, decreased inhibition, and reduced avoidance. Given the reciprocal interaction between relationship dysfunction and mental health problems, ketamine may also help alleviate relationship distress by directly treating clinical mental health symptoms. We then outline a proposed framework for ketamine-assisted couple therapy, addressing the application of KAP preparation, dosing, and integration to a dyadic intervention framework in a way that can be applied to different couple therapy modalities. This clinical framework for couples' KAP may be useful for clinicians and researchers working to improve the efficacy of couple therapy, particularly when one or both partners has accompanying mental health concerns.
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Affiliation(s)
- C. Khalifian
- Veterans Affairs San Diego Healthcare System, San Diego, CA, United States
- Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
| | - K. Rashkovsky
- Veterans Affairs San Diego Healthcare System, San Diego, CA, United States
- Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
| | - E. Mitchell
- Veterans Affairs San Diego Healthcare System, San Diego, CA, United States
- Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
| | - A. Bismark
- Veterans Affairs San Diego Healthcare System, San Diego, CA, United States
- Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
| | - A. C. Wagner
- Remedy, Toronto, ON, Canada
- Department of Psychology, Toronto Metropolitan University, Toronto, ON, Canada
| | - K. C. Knopp
- Veterans Affairs San Diego Healthcare System, San Diego, CA, United States
- Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
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11
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Chen MH, Su TP, Li CT, Lin WC, Wu HJ, Tsai SJ, Bai YM, Mao WC, Tu PC. Effects of melancholic features on positive and negative suicidal ideation in patients with treatment-resistant depression and strong suicidal ideation receiving low-dose ketamine infusion. Eur Arch Psychiatry Clin Neurosci 2024; 274:759-766. [PMID: 38052767 DOI: 10.1007/s00406-023-01735-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 11/24/2023] [Indexed: 12/07/2023]
Abstract
The role of melancholic features on the antisuicidal effect of 0.5 mg/kg ketamine infusion has remained unclear in patients with treatment-resistant depression (TRD) and strong suicidal ideation (SI). Whether ketamine diminishes suicidal ideation in patients with TRD-SI was also unknown. We enrolled 84 patients with TRD-SI, including 27 with melancholic features and 57 without, and then randomly administered a single infusion of 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) item 10, Columbia Suicide Severity Rating Scale-Ideation Severity Subscale (CSSRS-ISS), and self-reported Positive and Negative Suicide Ideation Inventory (PANSI) were used to assess suicidal symptoms from baseline to day 7. Generalized estimating equation models showed that only patients without melancholic features (MADRS item 10: infusion group effect, p = 0.017; CSSRS-ISS: infusion group × time effect, p = 0.008; PANSI-negative suicidal ideation: infusion group effect, p = 0.028) benefited from the antisuicidal effect of low-dose ketamine. The PANSI-positive ideation scores were higher in the ketamine group than in the midazolam group (p = 0.038) for patients with melancholic features. Additional studies are necessary to clarify the neuromechanisms underlying the ketamine-related positive effect against SI and antisuicidal effects among patients with TRD-SI. Additional studies are necessary to clarify the neuromechanisms underlying the ketamine-related positive effect against SI and antisuicidal effects among patients with TRD-SI.
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Affiliation(s)
- Mu-Hong Chen
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec.2, Shih-Pai Road, Beitou District, Taipei, 112, Taiwan.
- Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Tung-Ping Su
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec.2, Shih-Pai Road, Beitou District, Taipei, 112, Taiwan
- Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan
| | - Cheng-Ta Li
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec.2, Shih-Pai Road, Beitou District, Taipei, 112, Taiwan
- Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Chen Lin
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec.2, Shih-Pai Road, Beitou District, Taipei, 112, Taiwan
- Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hui-Ju Wu
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec.2, Shih-Pai Road, Beitou District, Taipei, 112, Taiwan
| | - Shih-Jen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec.2, Shih-Pai Road, Beitou District, Taipei, 112, Taiwan
- Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ya-Mei Bai
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec.2, Shih-Pai Road, Beitou District, Taipei, 112, Taiwan
- Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Chung Mao
- Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan
| | - Pei-Chi Tu
- Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec.2, Shih-Pai Road, Beitou District, Taipei, 112, Taiwan
- Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
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12
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Salvatore SV, Lambert PM, Benz A, Rensing NR, Wong M, Zorumski CF, Mennerick S. Periodic and aperiodic changes to cortical EEG in response to pharmacological manipulation. J Neurophysiol 2024; 131:529-540. [PMID: 38323322 PMCID: PMC11305649 DOI: 10.1152/jn.00445.2023] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/17/2024] [Accepted: 01/31/2024] [Indexed: 02/08/2024] Open
Abstract
Cortical electroencephalograms (EEGs) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/f) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than excitation/inhibition ratio may alter EEG parameters. Thus, to test the robustness of the aperiodic exponent as a predictor of excitation/inhibition ratio, we analyzed video-EEG during active exploration in mice of both sexes during various pharmacological manipulations with the fitting oscillations and one over f (FOOOF) algorithm. We found that GABAA receptor (GABAAR)-positive allosteric modulators increased the aperiodic exponent, consistent with the hypothesis that an increased exponent signals enhanced cortical inhibition, but other drugs (ketamine and GABAAR antagonists at subconvulsive doses) did not follow the prediction. To tilt excitation/inhibition ratio more selectively toward excitation, we suppressed the activity of parvalbumin-positive interneurons with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Contrary to our expectations, circuit disinhibition with the DREADD increased the aperiodic exponent. We conclude that the aperiodic exponent of EEG power spectra does not yield a universally reliable marker of cortical excitation/inhibition ratio.NEW & NOTEWORTHY Neuropsychiatric illness may be associated with altered excitation/inhibition balance. A single electroencephalogram (EEG) parameter, the aperiodic exponent of power spectra, may predict the ratio between excitation and inhibition. Here, we use cortical EEGs in mice to evaluate this hypothesis, using pharmacological manipulations of known mechanism. We show that the aperiodic exponent of EEG power spectra is not a reliable marker of excitation/inhibition ratio. Thus, alternative markers of this ratio must be sought.
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Affiliation(s)
- Sofia V Salvatore
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
| | - Peter M Lambert
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
- Medical Scientist Training Program, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
| | - Ann Benz
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
| | - Nicholas R Rensing
- Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
| | - Michael Wong
- Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
| | - Charles F Zorumski
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
- Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
| | - Steven Mennerick
- Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
- Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
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13
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Rawat R, Tunc-Ozcan E, Dunlop S, Tsai YH, Li F, Bertossi R, Peng CY, Kessler JA. Ketamine's rapid and sustained antidepressant effects are driven by distinct mechanisms. Cell Mol Life Sci 2024; 81:105. [PMID: 38413417 PMCID: PMC10899278 DOI: 10.1007/s00018-024-05121-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 01/03/2024] [Accepted: 01/08/2024] [Indexed: 02/29/2024]
Abstract
Administration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine's rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis. Treatment with six doses of ketamine over two weeks doubled the duration of behavioral effects after the final ketamine injection. However, unlike ketamine's rapid effects, this more sustained behavioral effect did not correlate with increased immature neuron activity but instead correlated with increased numbers of calretinin-positive and doublecortin-positive immature neurons. This increase in neurogenesis was associated with a decrease in bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Injection of a BMP4-expressing lentivirus into the dentate gyrus maintained BMP signaling in the niche and blocked the sustained - but not the rapid - behavioral effects of ketamine, indicating that decreased BMP signaling is necessary for ketamine's sustained effects. Thus, although the rapid effects of ketamine result from increased activity of immature neurons in the dentate gyrus without requiring an increase in neurogenesis, ketamine's sustained effects require a decrease in BMP signaling and increased neurogenesis along with increased neuron activity. Understanding ketamine's dual mechanisms of action should help with the development of new rapid-acting therapies that also have safe, reliable, and sustained effects.
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Affiliation(s)
- Radhika Rawat
- Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Ward 10-233, Chicago, IL, 60611, USA.
| | - Elif Tunc-Ozcan
- Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Ward 10-233, Chicago, IL, 60611, USA
| | - Sara Dunlop
- Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Ward 10-233, Chicago, IL, 60611, USA
| | - Yung-Hsu Tsai
- Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Ward 10-233, Chicago, IL, 60611, USA
| | - Fangze Li
- Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Ward 10-233, Chicago, IL, 60611, USA
| | - Ryan Bertossi
- Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Ward 10-233, Chicago, IL, 60611, USA
| | - Chian-Yu Peng
- Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Ward 10-233, Chicago, IL, 60611, USA
| | - John A Kessler
- Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Ward 10-233, Chicago, IL, 60611, USA
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14
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Ren L. The mechanistic basis for the rapid antidepressant-like effects of ketamine: From neural circuits to molecular pathways. Prog Neuropsychopharmacol Biol Psychiatry 2024; 129:110910. [PMID: 38061484 DOI: 10.1016/j.pnpbp.2023.110910] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023]
Abstract
Conventional antidepressants that target monoaminergic receptors require several weeks to be efficacious. This lag represents a significant problem in the currently available treatments for serious depression. Ketamine, acting as an N-methyl-d-aspartate receptor antagonist, was shown to have rapid antidepressant-like effects, marking a significant advancement in the study of mood disorders. However, serious side effects and adverse reactions limit its clinical use. Considering the limitations of ketamine, it is crucial to further define the network targets of ketamine. The rapid action of ketamine an as antidepressant is thought to be mediated by the glutamate system. It is believed that synaptic plasticity is essential for the rapid effects of ketamine as an antidepressant. Other mechanisms include the involvement of the γ-aminobutyric acidergic (GABAergic), 5-HTergic systems, and recent studies have linked astrocytes to ketamine's rapid antidepressant-like effects. The interactions between these systems exert a synergistic rapid antidepressant effect through neural circuits and molecular mechanisms. Here, we discuss the neural circuits and molecular mechanisms underlying the action of ketamine. This work will help explain how molecular and neural targets are responsible for the effects of rapidly acting antidepressants and will aid in the discovery of new therapeutic approaches for major depressive disorder.
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Affiliation(s)
- Li Ren
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Sichuan Chengdu 611137, China.
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15
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Hanson JE, Yuan H, Perszyk RE, Banke TG, Xing H, Tsai MC, Menniti FS, Traynelis SF. Therapeutic potential of N-methyl-D-aspartate receptor modulators in psychiatry. Neuropsychopharmacology 2024; 49:51-66. [PMID: 37369776 PMCID: PMC10700609 DOI: 10.1038/s41386-023-01614-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/24/2023] [Accepted: 05/15/2023] [Indexed: 06/29/2023]
Abstract
N-methyl-D-aspartate (NMDA) receptors mediate a slow component of excitatory synaptic transmission, are widely distributed throughout the central nervous system, and regulate synaptic plasticity. NMDA receptor modulators have long been considered as potential treatments for psychiatric disorders including depression and schizophrenia, neurodevelopmental disorders such as Rett Syndrome, and neurodegenerative conditions such as Alzheimer's disease. New interest in NMDA receptors as therapeutic targets has been spurred by the findings that certain inhibitors of NMDA receptors produce surprisingly rapid and robust antidepressant activity by a novel mechanism, the induction of changes in the brain that well outlast the presence of drug in the body. These findings are driving research into an entirely new paradigm for using NMDA receptor antagonists in a host of related conditions. At the same time positive allosteric modulators of NMDA receptors are being pursued for enhancing synaptic function in diseases that feature NMDA receptor hypofunction. While there is great promise, developing the therapeutic potential of NMDA receptor modulators must also navigate the potential significant risks posed by the use of such agents. We review here the emerging pharmacology of agents that target different NMDA receptor subtypes, offering new avenues for capturing the therapeutic potential of targeting this important receptor class.
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Affiliation(s)
- Jesse E Hanson
- Department of Neuroscience, Genentech Inc., South San Francisco, CA, 94080, USA
| | - Hongjie Yuan
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Riley E Perszyk
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Tue G Banke
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Hao Xing
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Ming-Chi Tsai
- Department of Neuroscience, Genentech Inc., South San Francisco, CA, 94080, USA
| | - Frank S Menniti
- MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, 02881, USA.
| | - Stephen F Traynelis
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
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16
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Tsugiyama LE, Macedo Moraes RC, Cavalcante Moraes YA, Francis-Oliveira J. Promising new pharmacological targets for depression: The search for efficacy. Drug Discov Today 2023; 28:103804. [PMID: 37865307 DOI: 10.1016/j.drudis.2023.103804] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 08/31/2023] [Accepted: 10/16/2023] [Indexed: 10/23/2023]
Abstract
Pharmacological treatment of major depressive disorder (MDD) still relies on the use of serotonergic drugs, despite their limited efficacy. A few mechanistically new drugs have been developed in recent years, but many fail in clinical trials. Several hypotheses have been proposed to explain MDD pathophysiology, indicating that physiological processes such as neuroplasticity, circadian rhythms, and metabolism are potential targets. Here, we review the current state of pharmacological treatments for MDD, as well as the preclinical and clinical evidence for an antidepressant effect of molecules that target non-serotonergic systems. We offer some insights into the challenges facing the development of new antidepressant drugs, and the prospect of finding more effectiveness for each target discussed.
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Affiliation(s)
- Lucila Emiko Tsugiyama
- Kansai Medical University, Graduate School of Medicine, iPS Cell Applied Medicine, Hirakata, Osaka, Japan
| | - Ruan Carlos Macedo Moraes
- University of Alabama at Birmingham, Department of Psychiatry and Behavioral Neurobiology, Birmingham, AL, USA; Biomedical Sciences Institute, Department of Human Physiology, Sao Paulo University, Sao Paulo, Brazil
| | | | - Jose Francis-Oliveira
- University of Alabama at Birmingham, Department of Psychiatry and Behavioral Neurobiology, Birmingham, AL, USA; Biomedical Sciences Institute, Department of Human Physiology, Sao Paulo University, Sao Paulo, Brazil.
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17
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Hilal F, Jeanblanc J, Naassila M. [Interest and mechanisms of action of ketamine in alcohol addiction- A review of clinical and preclinical studies]. Biol Aujourdhui 2023; 217:161-182. [PMID: 38018944 DOI: 10.1051/jbio/2023028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Indexed: 11/30/2023]
Abstract
Alcohol Use Disorder (AUD) is a psychiatric condition characterized by chronic and excessive drinking despite negative consequences on overall health and social or occupational functioning. There are currently limited treatment options available for AUD, and the effects size and the response rates to these treatments are often low to moderate. The World Health Organization has identified the development of medications to treat AUD as one of its 24 priorities. This past decade was marked by a renewed interest in psychedelic use in psychiatry. At the centre of this renaissance, ketamine, an atypical psychedelic already used in the treatment of major depression, is an NMDA receptor antagonist that exists as a racemic compound made of two enantiomers, S-ketamine, and R-ketamine. Each form can be metabolized into different metabolites, some of which having antidepressant properties. In this article, we review both clinical and preclinical studies on ketamine and its metabolites in the treatment of AUD. Preclinical as well as clinical studies have revealed that ketamine is effective in reducing withdrawal symptoms and alcohol craving. Convergent data showed that antidepressant properties of ketamine largely contribute to the decreased likelihood of alcohol relapse, especially in patients undergoing ketamine-assisted psychotherapies. Its effectiveness is believed to be linked with its ability to regulate the glutamatergic pathway, enhance neuroplasticity, rewire brain resting state network functional connectivity and decrease depressive-like states. However, it remains to further investigate (i) why strong differences exist between male and female responses in preclinical studies and (ii) the respective roles of each of the metabolites in the ketamine effects in both genders. Interestingly, current studies are also focusing on ketamine addiction and the comorbidity between alcohol addiction and depression occurring more frequently in females.
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Affiliation(s)
- Fahd Hilal
- Groupe de recherche sur l'alcool et les pharmacodépendances, INSERM U1247, CURS, Amiens, France
| | - Jérôme Jeanblanc
- Groupe de recherche sur l'alcool et les pharmacodépendances, INSERM U1247, CURS, Amiens, France
| | - Mickaël Naassila
- Groupe de recherche sur l'alcool et les pharmacodépendances, INSERM U1247, CURS, Amiens, France
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18
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Salvatore SV, Lambert PM, Benz A, Rensing NR, Wong M, Zorumski CF, Mennerick S. Periodic and aperiodic changes to cortical EEG in response to pharmacological manipulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.21.558828. [PMID: 37790570 PMCID: PMC10542500 DOI: 10.1101/2023.09.21.558828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
Cortical electroencephalograms (EEG) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/ f ) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition (E/I) balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than E/I ratio may alter EEG parameters. Thus, to test the robustness of the aperiodic exponent as a predictor of E/I ratio, we analyzed active exploration in mice using video EEG following various pharmacological manipulations with the Fitting Oscillations & One Over F (FOOOF) algorithm. We found that GABA A receptor (GABA A R) positive allosteric modulators increased the aperiodic exponent, consistent with the hypothesis that an increased exponent signals enhanced cortical inhibition, but other drugs (ketamine and GABA A R antagonists at sub-convulsive doses) did not follow the prediction. To tilt E/I ratio more selectively toward excitation, we suppressed the activity of parvalbumin (PV) interneurons with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Contrary to our expectations and studies demonstrating increased cortical activity following PV suppression, circuit disinhibition with the DREADD increased the aperiodic exponent. We conclude that the aperiodic exponent of EEG power spectra does not yield a universally reliable marker of E/I ratio. Alternatively, the concept of E/I state may be sufficiently oversimplified that it cannot be mapped readily onto an EEG parameter. Significance StateBment Neuropsychiatric illness is widely prevalent and debilitating. Causes are not well understood, but some hypotheses point toward altered excitation/inhibition (E/I) balance. Here, we use cortical electroencephalograms (EEG) in mice, given applicability of cortical EEG across species, and evaluate the impact of validated drugs, including anxiolytics (pentobarbital and diazepam), along with novel rapid-acting antidepressants (ketamine and allopregnanolone). We focus on analyzing the aperiodic component of EEG power spectra, which may be associated with changes in E/I ratio. We show that aperiodic exponent of EEG power spectra is not a reliable marker of E/I ratio. Moreover, the concept of E/I ratio may be too broad and complex to be defined by an EEG parameter.
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Zhou JS, Peng GF, Liang WD, Chen Z, Liu YY, Wang BY, Guo ML, Deng YL, Ye JM, Zhong ML, Wang LF. Recent advances in the study of anesthesia-and analgesia-related mechanisms of S-ketamine. Front Pharmacol 2023; 14:1228895. [PMID: 37781698 PMCID: PMC10539608 DOI: 10.3389/fphar.2023.1228895] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 09/04/2023] [Indexed: 10/03/2023] Open
Abstract
Ketamine is a racemic mixture of equal amounts of R-ketamine and S-ketamine and is well known to anesthesiologists for its unique dissociative anesthetic properties. The pharmacological properties of ketamine, namely, its sympathetic excitation, mild respiratory depression, and potent analgesia, are still highly valued in its use as an anesthetic for some patients. In particular, since its advent, S-ketamine has been widely used as an anesthetic in many countries due to its increased affinity for NMDA receptors and its enhanced anesthetic and analgesic effects. However, the anesthetic and analgesic mechanisms of S-ketamine are not fully understood. In addition to antagonizing NMDA receptors, a variety of other receptors or channels may be involved, but there are no relevant mechanistic summaries in the literature. Therefore, the purpose of this paper is to review the mechanisms of action of S-ketamine on relevant receptors and systems in the body that result in its pharmacological properties, such as anesthesia and analgesia, with the aim of providing a reference for its clinical applications and research.
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Affiliation(s)
- Jian-shun Zhou
- The First Clinical Medical College of Gannan Medical University, Ganzhou, China
| | - Guan-fa Peng
- The First Clinical Medical College of Gannan Medical University, Ganzhou, China
| | - Wei-dong Liang
- Department of Anesthesiology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Anesthesiology, Ganzhou, China
| | - Zhen Chen
- The First Clinical Medical College of Gannan Medical University, Ganzhou, China
| | - Ying-ying Liu
- The First Clinical Medical College of Gannan Medical University, Ganzhou, China
| | - Bing-yu Wang
- The First Clinical Medical College of Gannan Medical University, Ganzhou, China
| | - Ming-ling Guo
- The First Clinical Medical College of Gannan Medical University, Ganzhou, China
| | - Yun-ling Deng
- Department of Anesthesiology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Anesthesiology, Ganzhou, China
| | - Jun-ming Ye
- Department of Anesthesiology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Anesthesiology, Ganzhou, China
| | - Mao-lin Zhong
- Department of Anesthesiology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Anesthesiology, Ganzhou, China
| | - Li-feng Wang
- Department of Anesthesiology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Anesthesiology, Ganzhou, China
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20
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Cai M, Zhu Y, Shanley MR, Morel C, Ku SM, Zhang H, Shen Y, Friedman AK, Han MH. HCN channel inhibitor induces ketamine-like rapid and sustained antidepressant effects in chronic social defeat stress model. Neurobiol Stress 2023; 26:100565. [PMID: 37664876 PMCID: PMC10468802 DOI: 10.1016/j.ynstr.2023.100565] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 09/05/2023] Open
Abstract
Repeated, long-term (weeks to months) exposure to standard antidepressant medications is required to achieve treatment efficacy. In contrast, acute ketamine quickly improves mood for an extended time. Recent work implicates that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are involved in mediating ketamine's antidepressant effects. In this study, we directly targeted HCN channels and achieved ketamine-like rapid and sustained antidepressant efficacy. Our in vitro electrophysiological recordings first showed that HCN inhibitor DK-AH 269 (also called cilobradine) decreased the pathological HCN-mediated current (Ih) and abnormal hyperactivity of ventral tegmental area (VTA) dopamine (DA) neurons in a depressive-like model produced by chronic social defeat stress (CSDS). Our in vivo studies further showed that acute intra-VTA or acute systemic administration of DK-AH 269 normalized social behavior and rescued sucrose preference in CSDS-susceptible mice. The single-dose of DK-AH 269, both by intra-VTA microinfusion and intraperitoneal (ip) approaches, could produce an extended 13-day duration of antidepressant-like efficacy. Animals treated with acute DK-AH 269 spent less time immobile than vehicle-treated mice during forced swim test. A social behavioral reversal lasted up to 13 days following the acute DK-AH 269 ip injection, and this rapid and sustained antidepressant-like response is paralleled with a single-dose treatment of ketamine. This study provides a novel ion channel target for acutely acting, long-lasting antidepressant-like effects.
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Affiliation(s)
- Min Cai
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yingbo Zhu
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- China Shenzhen Naowunao Network Technology Co.,Ltd., Shenzhen, Guangdong, China
| | - Mary Regis Shanley
- Department of Biological Sciences, Hunter College, Biology and Biochemistry PhD Program, Graduate Center, The City University of New York, New York, NY, USA
| | - Carole Morel
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stacy M. Ku
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hongxing Zhang
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yuan Shen
- Anesthesia and Brain Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Allyson K. Friedman
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ming-Hu Han
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Shenzhen, Guangdong, China
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21
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Mingardi J, Ndoj E, Bonifacino T, Misztak P, Bertoli M, La Via L, Torazza C, Russo I, Milanese M, Bonanno G, Popoli M, Barbon A, Musazzi L. Functional and Molecular Changes in the Prefrontal Cortex of the Chronic Mild Stress Rat Model of Depression and Modulation by Acute Ketamine. Int J Mol Sci 2023; 24:10814. [PMID: 37445990 DOI: 10.3390/ijms241310814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/23/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Stress is a primary risk factor in the onset of neuropsychiatric disorders, including major depressive disorder (MDD). We have previously used the chronic mild stress (CMS) model of depression in male rats to show that CMS induces morphological, functional, and molecular changes in the hippocampus of vulnerable animals, the majority of which were recovered using acute subanesthetic ketamine in just 24 h. Here, we focused our attention on the medial prefrontal cortex (mPFC), a brain area regulating emotional and cognitive functions, and asked whether vulnerability/resilience to CMS and ketamine antidepressant effects were associated with molecular and functional changes in the mPFC of rats. We found that most alterations induced by CMS in the mPFC were selectively observed in stress-vulnerable animals and were rescued by acute subanesthetic ketamine, while others were found only in resilient animals or were induced by ketamine treatment. Importantly, only a few of these modifications were also previously demonstrated in the hippocampus, while most are specific to mPFC. Overall, our results suggest that acute antidepressant ketamine rescues brain-area-specific glutamatergic changes induced by chronic stress.
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Affiliation(s)
- Jessica Mingardi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Elona Ndoj
- Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
| | - Tiziana Bonifacino
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, 16148 Genoa, Italy
- Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), 56122 Pisa, Italy
| | - Paulina Misztak
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Matteo Bertoli
- Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
| | - Luca La Via
- Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
| | - Carola Torazza
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, 16148 Genoa, Italy
| | - Isabella Russo
- Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
- Genetics Unit, IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy
| | - Marco Milanese
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, 16148 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Giambattista Bonanno
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, 16148 Genoa, Italy
| | - Maurizio Popoli
- Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, 20133 Milano, Italy
| | - Alessandro Barbon
- Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
| | - Laura Musazzi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
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22
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Kim JW, Suzuki K, Kavalali ET, Monteggia LM. Bridging rapid and sustained antidepressant effects of ketamine. Trends Mol Med 2023; 29:364-375. [PMID: 36907686 PMCID: PMC10101916 DOI: 10.1016/j.molmed.2023.02.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/05/2023] [Accepted: 02/15/2023] [Indexed: 03/12/2023]
Abstract
Acute administration of (R,S)-ketamine (ketamine) produces rapid antidepressant effects that in some patients can be sustained for several days to more than a week. Ketamine blocks N-methyl-d-asparate (NMDA) receptors (NMDARs) to elicit specific downstream signaling that induces a novel form of synaptic plasticity in the hippocampus that has been linked to the rapid antidepressant action. These signaling events lead to subsequent downstream transcriptional changes that are involved in the sustained antidepressant effects. Here we review how ketamine triggers this intracellular signaling pathway to mediate synaptic plasticity which underlies the rapid antidepressant effects and links it to downstream signaling and the sustained antidepressant effects.
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Affiliation(s)
- Ji-Woon Kim
- Department of Pharmacology and the Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240, USA; College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Regulatory Science, Gradaute School, Kyung Hee University, Seoul, Republic of Korea; Institute of Regulatory Innovation through Science, Kyung Hee University, Seoul, Republic of Korea
| | - Kanzo Suzuki
- Department of Pharmacology and the Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240, USA; Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Katsushika-ku, Japan
| | - Ege T Kavalali
- Department of Pharmacology and the Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240, USA
| | - Lisa M Monteggia
- Department of Pharmacology and the Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240, USA.
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23
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Zimbelman AR, Wong B, Murray CH, Wolf ME, Stefanik MT. Dopamine D1 and NMDA receptor co-regulation of protein translation in cultured nucleus accumbens neurons. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.02.535293. [PMID: 37034633 PMCID: PMC10081306 DOI: 10.1101/2023.04.02.535293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/11/2023]
Abstract
Protein translation is essential for some forms of synaptic plasticity. We used nucleus accumbens (NAc) medium spiny neurons (MSN), co-cultured with cortical neurons to restore excitatory synapses, to examine whether dopamine modulates protein translation in NAc MSN. FUNCAT was used to measure translation in MSNs under basal conditions and after disinhibiting excitatory transmission using the GABAA receptor antagonist bicuculline (2 hr). Under basal conditions, translation was not altered by the D1-class receptor (D1R) agonist SKF81297 or the D2-class receptor (D2R) agonist quinpirole. Bicuculline alone robustly increased translation. This was reversed by quinpirole but not SKF81297. It was also reversed by co-incubation with the D1R antagonist SCH23390, but not the D2R antagonist eticlopride, suggesting dopaminergic tone at D1Rs. This was surprising because no dopamine neurons are present. An alternative explanation is that bicuculline activates translation by increasing glutamate tone at NMDA receptors (NMDAR) within D1R/NMDAR heteromers, which have been described in other cell types. Supporting this, immunocytochemistry and proximity ligation assays revealed D1/NMDAR heteromers on NAc cells both in vitro and in vivo. Further, bicuculline's effect was reversed to the same extent by SCH23390 alone, the NMDAR antagonist APV alone, or SCH23390+APV. These results suggest that: 1) excitatory synaptic transmission stimulates translation in NAc MSNs, 2) this is opposed when glutamate activates D1R/NMDAR heteromers, even in the absence of dopamine, and 3) antagonist occupation of D1Rs within the heteromers prevents their activation. Our study is the first to suggest a role for D2 receptors and D1R/NMDAR heteromers in regulating protein translation.
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Affiliation(s)
- Alexa R. Zimbelman
- Department of Psychology and Neuroscience, North Central College, Naperville, IL 60540
| | - Benjamin Wong
- Department of Psychology and Neuroscience, North Central College, Naperville, IL 60540
| | - Conor H. Murray
- Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064
- Present address: Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL
| | - Marina E. Wolf
- Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064
- These authors contributed equally
- Present address: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97212
| | - Michael T. Stefanik
- Department of Psychology and Neuroscience, North Central College, Naperville, IL 60540
- Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064
- These authors contributed equally
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24
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Griffiths JJ, Zarate CA, Rasimas JJ. Existing and Novel Biological Therapeutics in Suicide Prevention. FOCUS (AMERICAN PSYCHIATRIC PUBLISHING) 2023; 21:225-232. [PMID: 37201148 PMCID: PMC10172549 DOI: 10.1176/appi.focus.23021003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
We summarize outcomes for several pharmacologic and neurostimulatory approaches that have been considered potential treatments to reduce suicide risk, namely, by reducing suicide deaths, attempts, and ideation in various clinical populations. Available treatments include clozapine, lithium, antidepressants, antipsychotics, electroconvulsive therapy, and transcranial magnetic stimulation. The novel repurposing of ketamine as a potential suicide risk-mitigating agent in the acute setting is also discussed. Research pathways to better understand and treat suicidal ideation and behavior from a neurobiological perspective are proposed in light of this foundation of information and the limitations and challenges inherent in suicide research. Such pathways include trials of fast-acting medications, registry approaches to identify appropriate patients for trials, identification of biomarkers, neuropsychological vulnerabilities, and endophenotypes through the study of known suicide risk-mitigating agents in hope of determining mechanisms of pathophysiology and the action of protective biological interventions. Reprinted from Am J Prev Med 2014; 47:S195-S203, with permission from Elsevier. Copyright © 2014.
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Affiliation(s)
- Joshua J Griffiths
- From the Department of Psychiatry (Griffiths), University of Colorado, Denver, Colorado; Experimental Therapeutics and Pathophysiology Branch (Zarate, Rasimas), Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, Maryland; and Departments of Psychiatry and Emergency Medicine (Rasimas), Penn State College of Medicine, Hershey, Pennsylvania
| | - Carlos A Zarate
- From the Department of Psychiatry (Griffiths), University of Colorado, Denver, Colorado; Experimental Therapeutics and Pathophysiology Branch (Zarate, Rasimas), Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, Maryland; and Departments of Psychiatry and Emergency Medicine (Rasimas), Penn State College of Medicine, Hershey, Pennsylvania
| | - J J Rasimas
- From the Department of Psychiatry (Griffiths), University of Colorado, Denver, Colorado; Experimental Therapeutics and Pathophysiology Branch (Zarate, Rasimas), Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, Maryland; and Departments of Psychiatry and Emergency Medicine (Rasimas), Penn State College of Medicine, Hershey, Pennsylvania
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25
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Marguilho M, Figueiredo I, Castro-Rodrigues P. A unified model of ketamine's dissociative and psychedelic properties. J Psychopharmacol 2023; 37:14-32. [PMID: 36527355 PMCID: PMC9834329 DOI: 10.1177/02698811221140011] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Ketamine is an N-methyl-d-aspartate antagonist which is increasingly being researched and used as a treatment for depression. In low doses, it can cause a transitory modification in consciousness which was classically labelled as 'dissociation'. However, ketamine is also commonly classified as an atypical psychedelic and it has been recently reported that ego dissolution experiences during ketamine administration are associated with greater antidepressant response. Neuroimaging studies have highlighted several similarities between the effects of ketamine and those of serotonergic psychedelics in the brain; however, no unified account has been proposed for ketamine's multi-level effects - from molecular to network and psychological levels. Here, we propose that the fast, albeit transient, antidepressant effects observed after ketamine infusions are mainly driven by its acute modulation of reward circuits and sub-acute increase in neuroplasticity, while its dissociative and psychedelic properties are driven by dose- and context-dependent disruption of large-scale functional networks. Computationally, as nodes of the salience network (SN) represent high-level priors about the body ('minimal' self) and nodes of the default-mode network (DMN) represent the highest-level priors about narrative self-experience ('biographical' self), we propose that transitory SN desegregation and disintegration accounts for ketamine's 'dissociative' state, while transitory DMN desegregation and disintegration accounts for ketamine's 'psychedelic' state. In psychedelic-assisted psychotherapy, a relaxation of the highest-level beliefs with psychotherapeutic support may allow a revision of pathological self-representation models, for which neuroplasticity plays a permissive role. Our account provides a multi-level rationale for using the psychedelic properties of ketamine to increase its long-term benefits.
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Affiliation(s)
| | | | - Pedro Castro-Rodrigues
- Centro Hospitalar Psiquiátrico de Lisboa, Lisbon, Portugal,NOVA Medical School, NMS, Universidade Nova de Lisboa, Lisbon, Portugal,Pedro Castro-Rodrigues, Centro Hospitalar Psiquiátrico de Lisboa, Avenida do Brasil, 53, Lisbon, 1749-002, Portugal.
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26
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Alnefeesi Y, Chen-Li D, Krane E, Jawad MY, Rodrigues NB, Ceban F, Di Vincenzo JD, Meshkat S, Ho RCM, Gill H, Teopiz KM, Cao B, Lee Y, McIntyre RS, Rosenblat JD. Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. J Psychiatr Res 2022; 151:693-709. [PMID: 35688035 DOI: 10.1016/j.jpsychires.2022.04.037] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 04/10/2022] [Accepted: 04/26/2022] [Indexed: 12/29/2022]
Abstract
Ketamine is a promising therapeutic option in treatment-resistant depression (TRD). The acute efficacy of ketamine in TRD has been demonstrated in replicated randomised-controlled trials (RCTs), but the generalizability of RCT data to real-world practice is limited. To this end, we conducted a systematic review (Search date: 25/12/2021; 1482 records identified) and meta-analysis of studies evaluating the real-world clinical effectiveness of ketamine in TRD patients. Four overlapping syntheses (Total n = 2665 patients; k = 79 studies) and 32 meta-regressions (Total n = 2050; k = 37) were conducted. All results suggest that the mean antidepressant effect is substantial (mean ± 95% CI, % responded = 45 ± 10%; p< 0.0001, % remitted = 30 ± 5.9%; p< 0.0001, Hedges g of symptomatological improvement = 1.44 ± 0.609; p < 0.0001), but the effect varies considerably among patients. The more treatment-resistant cases were found to remit less often (p < 0.01), but no such effect on response was evident (p > 0.05). Meta-regressions also confirmed that the therapeutic effect does not significantly decline with repeated treatments (p > 0.05). These results demonstrate that even the most treatment-resistant patients may benefit from ketamine, and that mid-to-long term treatment is effective in many patients.
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Affiliation(s)
- Yazen Alnefeesi
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - David Chen-Li
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Ella Krane
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | | | - Nelson B Rodrigues
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Felicia Ceban
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada
| | - Joshua D Di Vincenzo
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Shakila Meshkat
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Roger C M Ho
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore
| | - Hartej Gill
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Kayla M Teopiz
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Bing Cao
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, 400715, PR China
| | - Yena Lee
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada
| | - Roger S McIntyre
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada
| | - Joshua D Rosenblat
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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27
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Drozdz SJ, Goel A, McGarr MW, Katz J, Ritvo P, Mattina GF, Bhat V, Diep C, Ladha KS. Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature. J Pain Res 2022; 15:1691-1706. [PMID: 35734507 PMCID: PMC9207256 DOI: 10.2147/jpr.s360733] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 04/20/2022] [Indexed: 11/23/2022] Open
Abstract
Currently, ketamine is used in treating multiple pain, mental health, and substance abuse disorders due to rapid-acting analgesic and antidepressant effects. Its limited short-term durability has motivated research into the potential synergistic actions between ketamine and psychotherapy to sustain benefits. This systematic review on ketamine-assisted psychotherapy (KAP) summarizes existing evidence regarding present-day practices. Through rigorous review, seventeen articles that included 603 participants were identified. From available KAP publications, it is apparent that combined treatments can, in specific circumstances, initiate and prolong clinically significant reductions in pain, anxiety, and depressive symptoms, while encouraging rapport and treatment engagement, and promoting abstinence in patients addicted to other substances. Despite much variance in how KAP is applied (route of ketamine administration, ketamine dosage/frequency, psychotherapy modality, overall treatment length), these findings suggest psychotherapy, provided before, during, and following ketamine sessions, can maximize and prolong benefits. Additional large-scale randomized control trials are warranted to understand better the mutually influential relationships between psychotherapy and ketamine in optimizing responsiveness and sustaining long-term benefits in patients with chronic pain. Such investigations will assist in developing standardized practices and maintenance programs.
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Affiliation(s)
- Sandra J Drozdz
- Department of Anesthesia, St. Michael's Hospital, Toronto, ON, Canada
| | - Akash Goel
- Department of Anesthesia, St. Michael's Hospital, Toronto, ON, Canada.,Department of Anesthesiology, Pain and Perioperative Medicine, Stanford University, Stanford, CA, USA.,Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada
| | - Matthew W McGarr
- Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Joel Katz
- Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada.,Department of Psychology, York University, Toronto, ON, Canada.,Department of Anesthesia and Pain Management, University Health Network, Toronto, ON, Canada.,School of Kinesiology and Health Science, York University, Toronto, ON, Canada
| | - Paul Ritvo
- Department of Psychology, York University, Toronto, ON, Canada.,School of Kinesiology and Health Science, York University, Toronto, ON, Canada
| | | | - Venkat Bhat
- Interventional Psychiatry Program, St. Michael's Hospital, Toronto, ON, Canada.,Department of Psychiatry, University of Toronto, Toronto, ON, Canada.,Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada
| | - Calvin Diep
- Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada
| | - Karim S Ladha
- Department of Anesthesia, St. Michael's Hospital, Toronto, ON, Canada.,Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada.,Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada
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28
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Sharafi A, Pakkhesal S, Fakhari A, Khajehnasiri N, Ahmadalipour A. Rapid treatments for depression: Endocannabinoid system as a therapeutic target. Neurosci Biobehav Rev 2022; 137:104635. [PMID: 35351488 DOI: 10.1016/j.neubiorev.2022.104635] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 03/19/2022] [Accepted: 03/20/2022] [Indexed: 12/16/2022]
Abstract
Current first-line treatments for major depressive disorder (MDD), i.e., antidepressant drugs and psychotherapy, show delayed onset of therapeutic effect as late as 2-3 weeks or more. In the clinic, the speed of beginning of the actions of antidepressant drugs or other interventions is vital for many reasons. Late-onset means that depression, its related disability, and the potential danger of suicide remain a threat for some patients. There are some rapid-acting antidepressant interventions, such as sleep deprivation, ketamine, acute exercise, which induce a significant response, ranging from a few hours to maximally one week, and most of them share a common characteristic that is the activation of the endocannabinoid (eCB) system. Activation of this system, i.e., augmentation of eCB signaling, appears to have anti-depressant-like actions. This article puts the idea forward that the activation of eCB signaling represents a critical mechanism of rapid-acting therapeutic interventions in MDD, and this system might contribute to the development of novel rapid-acting treatments for MDD.
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Affiliation(s)
- AmirMohammad Sharafi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Pakkhesal
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Fakhari
- Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazli Khajehnasiri
- Department of Biological Science, Faculty of Basic Science, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Ali Ahmadalipour
- Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
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29
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Glutamate Efflux across the Blood–Brain Barrier: New Perspectives on the Relationship between Depression and the Glutamatergic System. Metabolites 2022; 12:metabo12050459. [PMID: 35629963 PMCID: PMC9143347 DOI: 10.3390/metabo12050459] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/11/2022] [Accepted: 05/17/2022] [Indexed: 02/04/2023] Open
Abstract
Depression is a significant cause of disability and affects millions worldwide; however, antidepressant therapies often fail or are inadequate. Current medications for treating major depressive disorder can take weeks or months to reach efficacy, have troubling side effects, and are limited in their long-term capabilities. Recent studies have identified a new set of glutamate-based approaches, such as blood glutamate scavengers, which have the potential to provide alternatives to traditional antidepressants. In this review, we hypothesize as to the involvement of the glutamate system in the development of depression. We identify the mechanisms underlying glutamate dysregulation, offering new perspectives on the therapeutic modalities of depression with a focus on its relationship to blood–brain barrier (BBB) permeability. Ultimately, we conclude that in diseases with impaired BBB permeability, such as depression following stroke or traumatic brain injury, or in neurogenerative diseases, the glutamate system should be considered as a pathway to treatment. We propose that drugs such as blood glutamate scavengers should be further studied for treatment of these conditions.
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30
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Rawat R, Tunc-Ozcan E, McGuire TL, Peng CY, Kessler JA. Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice. Nat Commun 2022; 13:2650. [PMID: 35551462 PMCID: PMC9098911 DOI: 10.1038/s41467-022-30386-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 04/29/2022] [Indexed: 12/16/2022] Open
Abstract
Ketamine treatment decreases depressive symptoms within hours, but the mechanisms mediating these rapid antidepressant effects are unclear. Here, we demonstrate that activity of adult-born immature granule neurons (ABINs) in the mouse hippocampal dentate gyrus is both necessary and sufficient for the rapid antidepressant effects of ketamine. Ketamine treatment activates ABINs in parallel with its behavioral effects in both stressed and unstressed mice. Chemogenetic inhibition of ABIN activity blocks the antidepressant effects of ketamine, indicating that this activity is necessary for the behavioral effects. Conversely, chemogenetic activation of ABINs without any change in neuron numbers mimics both the cellular and the behavioral effects of ketamine, indicating that increased activity of ABINs is sufficient for rapid antidepressant effects. These findings thus identify a specific cell population that mediates the antidepressant actions of ketamine, indicating that ABINs can potentially be targeted to limit ketamine's side effects while preserving its therapeutic efficacy.
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Affiliation(s)
- Radhika Rawat
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
| | - Elif Tunc-Ozcan
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Tammy L McGuire
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Chian-Yu Peng
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - John A Kessler
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
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31
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Wang CS, Chanaday NL, Monteggia LM, Kavalali ET. Probing the segregation of evoked and spontaneous neurotransmission via photobleaching and recovery of a fluorescent glutamate sensor. eLife 2022; 11:e76008. [PMID: 35420542 PMCID: PMC9129874 DOI: 10.7554/elife.76008] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 04/08/2022] [Indexed: 11/13/2022] Open
Abstract
Synapses maintain both action potential-evoked and spontaneous neurotransmitter release; however, organization of these two forms of release within an individual synapse remains unclear. Here, we used photobleaching properties of iGluSnFR, a fluorescent probe that detects glutamate, to investigate the subsynaptic organization of evoked and spontaneous release in primary hippocampal cultures. In nonneuronal cells and neuronal dendrites, iGluSnFR fluorescence is intensely photobleached and recovers via diffusion of nonphotobleached probes with a time constant of ~10 s. After photobleaching, while evoked iGluSnFR events could be rapidly suppressed, their recovery required several hours. In contrast, iGluSnFR responses to spontaneous release were comparatively resilient to photobleaching, unless the complete pool of iGluSnFR was activated by glutamate perfusion. This differential effect of photobleaching on different modes of neurotransmission is consistent with a subsynaptic organization where sites of evoked glutamate release are clustered and corresponding iGluSnFR probes are diffusion restricted, while spontaneous release sites are broadly spread across a synapse with readily diffusible iGluSnFR probes.
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Affiliation(s)
- Camille S Wang
- Vanderbilt Brain Institute, Vanderbilt UniversityNashvilleUnited States
| | - Natali L Chanaday
- Department of Pharmacology, Vanderbilt UniversityNashvilleUnited States
| | - Lisa M Monteggia
- Vanderbilt Brain Institute, Vanderbilt UniversityNashvilleUnited States
- Department of Pharmacology, Vanderbilt UniversityNashvilleUnited States
| | - Ege T Kavalali
- Vanderbilt Brain Institute, Vanderbilt UniversityNashvilleUnited States
- Department of Pharmacology, Vanderbilt UniversityNashvilleUnited States
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32
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Sala N, Paoli C, Bonifacino T, Mingardi J, Schiavon E, La Via L, Milanese M, Tornese P, Datusalia AK, Rosa J, Facchinetti R, Frumento G, Carini G, Salerno Scarzella F, Scuderi C, Forti L, Barbon A, Bonanno G, Popoli M, Musazzi L. Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex. Front Pharmacol 2022; 13:759626. [PMID: 35370690 PMCID: PMC8968915 DOI: 10.3389/fphar.2022.759626] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 01/25/2022] [Indexed: 12/17/2022] Open
Abstract
Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites.
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Affiliation(s)
- Nathalie Sala
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy
| | - Caterina Paoli
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy.,School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Tiziana Bonifacino
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, Genoa, Italy
| | - Jessica Mingardi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Emanuele Schiavon
- Department of Biotechnology and Life Sciences, University of Insubria, Busto Arsizio, Italy
| | - Luca La Via
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Marco Milanese
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, Genoa, Italy
| | - Paolo Tornese
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy
| | - Ashok K Datusalia
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy.,Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, India
| | - Jessica Rosa
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy.,Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirao Preto, Brazil
| | - Roberta Facchinetti
- Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy
| | - Giulia Frumento
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, Genoa, Italy
| | - Giulia Carini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | | | - Caterina Scuderi
- Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy
| | - Lia Forti
- Department of Biotechnology and Life Sciences, University of Insubria, Busto Arsizio, Italy
| | - Alessandro Barbon
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Giambattista Bonanno
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Maurizio Popoli
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy
| | - Laura Musazzi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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33
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Ma X, Yang S, Zhang Z, Liu L, Shi W, Yang S, Li S, Cai X, Zhou Q. Rapid and sustained restoration of astrocytic functions by ketamine in depression model mice. Biochem Biophys Res Commun 2022; 616:89-94. [DOI: 10.1016/j.bbrc.2022.03.068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/14/2022] [Indexed: 11/16/2022]
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34
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Imaging the effect of ketamine on synaptic density (SV2A) in the living brain. Mol Psychiatry 2022; 27:2273-2281. [PMID: 35165397 PMCID: PMC9133063 DOI: 10.1038/s41380-022-01465-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 01/11/2022] [Accepted: 01/26/2022] [Indexed: 12/28/2022]
Abstract
The discovery of ketamine as a rapid and robust antidepressant marks the beginning of a new era in the treatment of psychiatric disorders. Ketamine is thought to produce rapid and sustained antidepressant effects through restoration of lost synaptic connections. We investigated this hypothesis in humans for the first time using positron emission tomography (PET) and [11C]UCB-J-a radioligand that binds to the synaptic vesicle protein 2A (SV2A) and provides an index of axon terminal density. Overall, we did not find evidence of a measurable effect on SV2A density 24 h after a single administration of ketamine in non-human primates, healthy controls (HCs), or individuals with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), despite a robust reduction in symptoms. A post-hoc, exploratory analysis suggests that patients with lower SV2A density at baseline may exhibit increased SV2A density 24 h after ketamine. This increase in SV2A was associated with a reduction in depression severity, as well as an increase in dissociative symptoms. These initial findings suggest that a restoration of synaptic connections in patients with lower SV2A at baseline may underlie ketamine's therapeutic effects, however, this needs replication in a larger sample. Further work is needed to build on these initial findings and further establish the nuanced pre- and post-synaptic mechanisms underpinning ketamine's therapeutic effects.
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35
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Kotkowska Z, Strzelecki D. Depression and Autoimmune Hypothyroidism—Their Relationship and the Effects of Treating Psychiatric and Thyroid Disorders on Changes in Clinical and Biochemical Parameters Including BDNF and Other Cytokines—A Systematic Review. Pharmaceuticals (Basel) 2022; 15:ph15040391. [PMID: 35455388 PMCID: PMC9025086 DOI: 10.3390/ph15040391] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 02/04/2023] Open
Abstract
Various autoimmune diseases, including autoimmune hypothyroidism (AHT), are associated with a higher risk of developing mood disorders throughout life. Depression is accompanied by the changes in the levels of inflammatory and trophic factors, including interleukins (IL-1beta, IL-2, IL-6), interferon alpha (IFN-alpha), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), and brain derived neurotrophic factor (BDNF). Disclosure of the relationship between the coexistence of depression and AHT indicates that the pathomechanism of depression may be related to the changes in the immune system, it is also possible that both conditions may be caused by the same immune processes. The above hypothesis is indirectly supported by the observations that the treatment with both antidepressants and levothyroxine leads to a decrease in the levels of proinflammatory cytokines with an increase in BDNF concentrations, simultaneously correlating with an improvement in the clinical parameters. However, so far there are no long-term studies determining the causal relationship between depression, thyroid autoantibodies, and cytokine profile, which could bring us closer to understanding the interrelationships between them and facilitate the use of an adequate pharmacotherapy, not necessarily psychiatric. We consider the above issues to be insufficiently investigated but of great importance. This article is an overview of the available literature as well as an introduction to our research project.
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36
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Leung E, Lau EW, Liang A, de Dios C, Suchting R, Östlundh L, Masdeu JC, Fujita M, Sanches M, Soares JC, Selvaraj S. Alterations in brain synaptic proteins and mRNAs in mood disorders: a systematic review and meta-analysis of postmortem brain studies. Mol Psychiatry 2022; 27:1362-1372. [PMID: 35022529 DOI: 10.1038/s41380-021-01410-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 11/19/2021] [Accepted: 11/26/2021] [Indexed: 11/09/2022]
Abstract
The pathophysiological mechanisms underlying bipolar (BD) and major depressive disorders (MDD) are multifactorial but likely involve synaptic dysfunction and dysregulation. There are multiple synaptic proteins but three synaptic proteins, namely SNAP-25, PSD-95, and synaptophysin, have been widely studied for their role in synaptic function in human brain postmortem studies in BD and MDD. These studies have yielded contradictory results, possibly due to the small sample size and sourcing material from different cortical regions of the brain. We performed a systematic review and meta-analysis to understand the role of these three synaptic proteins and other synaptic proteins, messenger RNA (mRNA) and their regional localizations in BD and MDD. A systematic literature search was conducted and the review is reported in accordance with the MOOSE Guidelines. Meta-analysis was performed to compare synaptic marker levels between BD/MDD groups and controls separately. 1811 papers were identified in the literature search and screened against the preset inclusion and exclusion criteria. A total of 72 studies were screened in the full text, of which 47 were identified as eligible to be included in the systematic review. 24 of these 47 papers were included in the meta-analysis. The meta-analysis indicated that SNAP-25 protein levels were significantly lower in BD. On average, PSD-95 mRNA levels were lower in BD, and protein levels of SNAP-25, PSD-95, and syntaxin were lower in MDD. Localization analysis showed decreased levels of PSD-95 protein in the frontal cortex. We found specific alterations in synaptic proteins and RNAs in both BD and MDD. The review was prospectively registered online in PROSPERO international prospective register of systematic reviews, registration no. CRD42020196932.
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Affiliation(s)
- Edison Leung
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ethan W Lau
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Andi Liang
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Constanza de Dios
- Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Robert Suchting
- Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Linda Östlundh
- The National Medical Library, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Joseph C Masdeu
- Houston Methodist Neurological Institute, Houston, TX, USA.,Weill Cornell Medicine, New York, NY, USA
| | - Masahiro Fujita
- Weill Cornell Medicine, New York, NY, USA.,PET Core Facility, Houston Methodist Research Insitute, Houston, TX, USA
| | - Marsal Sanches
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jair C Soares
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Sudhakar Selvaraj
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA. .,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
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37
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Costi S, Han MH, Murrough JW. The Potential of KCNQ Potassium Channel Openers as Novel Antidepressants. CNS Drugs 2022; 36:207-216. [PMID: 35258812 DOI: 10.1007/s40263-021-00885-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/28/2021] [Indexed: 12/12/2022]
Abstract
Major depressive disorder (MDD) is a leading cause of disability worldwide and less than one-third of patients with MDD achieve stable remission of symptoms, despite currently available treatments. Although MDD represents a serious health problem, a complete understanding of the neurobiological mechanisms underlying this condition continues to be elusive. Accumulating evidence from preclinical and animal studies provides support for the antidepressant potential of modulators of KCNQ voltage-gated potassium (K+) channels. KCNQ K+ channels, through regulation of neuronal excitability and activity, contribute to neurophysiological mechanisms underlying stress resilience, and represent potential targets of drug discovery for depression. The present article focuses on the pharmacology and efficacy of KCNQ2/3 K+ channel openers as novel therapeutic agents for depressive disorders from initial studies conducted on animal models showing depressive-like behaviors to recent work in humans that examines the potential for KCNQ2/3 channel modulators as novel antidepressants. Data from preclinical work suggest that KCNQ-type K+ channels are an active mediator of stress resilience and KCNQ2/3 K+ channel openers show antidepressant efficacy. Similarly, evidence from clinical trials conducted in patients with MDD using the KCNQ2/3 channel opener ezogabine (retigabine) showed significant improvements in depressive symptoms and anhedonia. Overall, KCNQ channel openers appear a promising target for the development of novel therapeutics for the treatment of psychiatric disorders and specifically for MDD.
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Affiliation(s)
- Sara Costi
- Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1230, New York, NY, 10029, USA
| | - Ming-Hu Han
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Center for Affective Neuroscience, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - James W Murrough
- Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1230, New York, NY, 10029, USA. .,Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. .,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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38
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Alten B, Guzikowski NJ, Zurawski Z, Hamm HE, Kavalali ET. Presynaptic mechanisms underlying GABA B-receptor-mediated inhibition of spontaneous neurotransmitter release. Cell Rep 2022; 38:110255. [PMID: 35045279 PMCID: PMC8793855 DOI: 10.1016/j.celrep.2021.110255] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/15/2021] [Accepted: 12/21/2021] [Indexed: 01/08/2023] Open
Abstract
Inhibition of neurotransmitter release by neurotransmitter substances constitutes a fundamental means of neuromodulation. In contrast to well-delineated mechanisms that underlie inhibition of evoked release via suppression of voltage-gated Ca2+ channels, processes that underlie neuromodulatory inhibition of spontaneous release remain unclear. Here, we interrogated inhibition of spontaneous glutamate and GABA release by presynaptic metabotropic GABAB receptors. Our findings show that this inhibition relies on Gβγ subunit action at the membrane, and it is largely independent of presynaptic Ca2+ signaling for both forms of release. In the case of spontaneous glutamate release, inhibition requires Gβγ interaction with the C terminus of the key fusion machinery component SNAP25, and it is modulated by synaptotagmin-1. Inhibition of spontaneous GABA release, on the other hand, is independent of these pathways and likely requires alternative Gβγ targets at the presynaptic terminal.
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Affiliation(s)
- Baris Alten
- Department of Pharmacology, Vanderbilt University, 7130A MRB III 465 21st Avenue South, Nashville, TN 37240-7933, USA,Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240-7933, USA
| | - Natalie J. Guzikowski
- Department of Pharmacology, Vanderbilt University, 7130A MRB III 465 21st Avenue South, Nashville, TN 37240-7933, USA,Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240-7933, USA
| | - Zack Zurawski
- Department of Pharmacology, Vanderbilt University, 7130A MRB III 465 21st Avenue South, Nashville, TN 37240-7933, USA
| | - Heidi E. Hamm
- Department of Pharmacology, Vanderbilt University, 7130A MRB III 465 21st Avenue South, Nashville, TN 37240-7933, USA
| | - Ege T. Kavalali
- Department of Pharmacology, Vanderbilt University, 7130A MRB III 465 21st Avenue South, Nashville, TN 37240-7933, USA,Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240-7933, USA,Lead contact,Correspondence:
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39
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Wang CS, Kavalali ET, Monteggia LM. BDNF signaling in context: From synaptic regulation to psychiatric disorders. Cell 2022; 185:62-76. [PMID: 34963057 PMCID: PMC8741740 DOI: 10.1016/j.cell.2021.12.003] [Citation(s) in RCA: 309] [Impact Index Per Article: 103.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/10/2021] [Accepted: 12/02/2021] [Indexed: 01/09/2023]
Abstract
Brain-derived neurotrophic factor (BDNF) is a neuropeptide that plays numerous important roles in synaptic development and plasticity. While its importance in fundamental physiology is well established, studies of BDNF often produce conflicting and unclear results, and the scope of existing research makes the prospect of setting future directions daunting. In this review, we examine the importance of spatial and temporal factors on BDNF activity, particularly in processes such as synaptogenesis, Hebbian plasticity, homeostatic plasticity, and the treatment of psychiatric disorders. Understanding the fundamental physiology of when, where, and how BDNF acts and new approaches to control BDNF signaling in time and space can contribute to improved therapeutics and patient outcomes.
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Affiliation(s)
- Camille S Wang
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-2050, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA
| | - Ege T Kavalali
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-2050, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA
| | - Lisa M Monteggia
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-2050, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA.
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40
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Ren Z, Wang M, Aldhabi M, Zhang R, Liu Y, Liu S, Tang R, Chen Z. Low-dose S-ketamine exerts antidepressant-like effects via enhanced hippocampal synaptic plasticity in postpartum depression rats. Neurobiol Stress 2022; 16:100422. [PMID: 34977283 PMCID: PMC8686162 DOI: 10.1016/j.ynstr.2021.100422] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/11/2021] [Accepted: 12/13/2021] [Indexed: 11/05/2022] Open
Abstract
Rapid antidepressant effects of S-ketamine have repeatedly been confirmed in patients with depression, as well as in chronic unpredictable mild stress (CUMS) animal models. However, the pharmacological study of S-ketamine for anti-postpartum depression has not been considered. In this study, the classical method of reproductive hormone withdrawal was used to construct a rat model of postpartum depression (PPD). Subsequently, the study evaluated the effects of low-dose S-ketamine on behavior and synaptic plasticity, which is related to depression, in the hippocampus of PPD rats. Multiple behavioral tests were used to evaluate depression-like behaviors in PPD models. Synaptic plasticity of the hippocampus can be demonstrated by Western blot, Golgi staining, transmission electron microscopy, and electrophysiological recording. Our study provides insight into the role of low-dose S-ketamine in antidepressant as well as antianxiety and indicates that maintaining synaptic plasticity is a key target for S-ketamine therapy for postpartum depression induced by reproductive hormone withdrawal.
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Affiliation(s)
- Zhuoyu Ren
- Department of Anesthesiology, Qingdao Women and Children's Hospital of Qingdao University, Qingdao, Shandong, China
| | - Mingling Wang
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, Shandong, China
| | - Mokhtar Aldhabi
- Department of Urology of the Affiliated Hospital of Qingdao Binhai University, Qingdao, Shandong, China
| | - Rui Zhang
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, Shandong, China
| | - Yongxin Liu
- Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang, Shandong, China
| | - Shaoyan Liu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Rundong Tang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Zuolei Chen
- Department of Anesthesiology, Qingdao Women and Children's Hospital of Qingdao University, Qingdao, Shandong, China.,Department of Anesthesiology of the Affiliated Hospital of Qingdao Binhai University, Qingdao, Shandong, China
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41
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Khoodoruth MAS, Estudillo-Guerra MA, Pacheco-Barrios K, Nyundo A, Chapa-Koloffon G, Ouanes S. Glutamatergic System in Depression and Its Role in Neuromodulatory Techniques Optimization. Front Psychiatry 2022; 13:886918. [PMID: 35492692 PMCID: PMC9047946 DOI: 10.3389/fpsyt.2022.886918] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 03/28/2022] [Indexed: 11/17/2022] Open
Abstract
Depressive disorders are among the most common psychiatric conditions and contribute to significant morbidity. Even though the use of antidepressants revolutionized the management of depression and had a tremendous positive impact on the patient's outcome, a significant proportion of patients with major depressive disorder (MDD) show no or partial or response even with adequate treatment. Given the limitations of the prevailing monoamine hypothesis-based pharmacotherapy, glutamate and glutamatergic related pathways may offer an alternative and a complementary option for designing novel intervention strategies. Over the past few decades, there has been a growing interest in understanding the neurobiological underpinnings of glutamatergic dysfunctions in the pathogenesis of depressive disorders and the development of new pharmacological and non-pharmacological treatment options. There is a growing body of evidence for the efficacy of neuromodulation techniques, including transcranial magnetic stimulation, transcutaneous direct current stimulation, transcranial alternating current stimulation, and photo-biomodulation on improving connectivity and neuroplasticity associated with depression. This review attempts to revisit the role of glutamatergic neurotransmission in the etiopathogenesis of depressive disorders and review the current neuroimaging, neurophysiological and clinical evidence of these neuromodulation techniques in the pathophysiology and treatment of depression.
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Affiliation(s)
| | - Maria Anayali Estudillo-Guerra
- Department of Physical Medicine and Rehabilitation, Harvard Medical School, Spaulding Rehabilitation Hospital, Boston, MA, United States
| | - Kevin Pacheco-Barrios
- Neuromodulation Center and Center for Clinical Research Learning, Harvard Medical School, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Boston, MA, United States.,Universidad San Ignacio de Loyola, Vicerrectorado de Investigación, Unidad de Investigación para la Generación y Síntesis de Evidencias en Salud, Lima, Peru
| | - Azan Nyundo
- Department of Psychiatry and Mental Health, School of Medicine and Dental Health, The University of Dodoma, Dodoma, Tanzania
| | | | - Sami Ouanes
- Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar
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42
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Treatment resistance in psychiatry: state of the art and new directions. Mol Psychiatry 2022; 27:58-72. [PMID: 34257409 PMCID: PMC8960394 DOI: 10.1038/s41380-021-01200-3] [Citation(s) in RCA: 173] [Impact Index Per Article: 57.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/26/2021] [Accepted: 06/10/2021] [Indexed: 02/06/2023]
Abstract
Treatment resistance affects 20-60% of patients with psychiatric disorders; and is associated with increased healthcare burden and costs up to ten-fold higher relative to patients in general. Whilst there has been a recent increase in the proportion of psychiatric research focussing on treatment resistance (R2 = 0.71, p < 0.0001), in absolute terms this is less than 1% of the total output and grossly out of proportion to its prevalence and impact. Here, we provide an overview of treatment resistance, considering its conceptualisation, assessment, epidemiology, impact, and common neurobiological models. We also review new treatments in development and future directions. We identify 23 consensus guidelines on its definition, covering schizophrenia, major depressive disorder, bipolar affective disorder, and obsessive compulsive disorder (OCD). This shows three core components to its definition, but also identifies heterogeneity and lack of criteria for a number of disorders, including panic disorder, post-traumatic stress disorder, and substance dependence. We provide a reporting check-list to aid comparisons across studies. We consider the concept of pseudo-resistance, linked to poor adherence or other factors, and provide an algorithm for the clinical assessment of treatment resistance. We identify nine drugs and a number of non-pharmacological approaches being developed for treatment resistance across schizophrenia, major depressive disorder, bipolar affective disorder, and OCD. Key outstanding issues for treatment resistance include heterogeneity and absence of consensus criteria, poor understanding of neurobiology, under-investment, and lack of treatments. We make recommendations to address these issues, including harmonisation of definitions, and research into the mechanisms and novel interventions to enable targeted and personalised therapeutic approaches.
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43
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Mingardi J, La Via L, Tornese P, Carini G, Trontti K, Seguini M, Tardito D, Bono F, Fiorentini C, Elia L, Hovatta I, Popoli M, Musazzi L, Barbon A. miR-9-5p is involved in the rescue of stress-dependent dendritic shortening of hippocampal pyramidal neurons induced by acute antidepressant treatment with ketamine. Neurobiol Stress 2021; 15:100381. [PMID: 34458512 PMCID: PMC8379501 DOI: 10.1016/j.ynstr.2021.100381] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/03/2021] [Accepted: 08/07/2021] [Indexed: 12/12/2022] Open
Abstract
Converging clinical and preclinical evidence demonstrates that depressive phenotypes are associated with synaptic dysfunction and dendritic simplification in cortico-limbic glutamatergic areas. On the other hand, the rapid antidepressant effect of acute ketamine is consistently reported to occur together with the rescue of dendritic atrophy and reduction of spine number induced by chronic stress in the hippocampus and prefrontal cortex of animal models of depression. Nevertheless, the molecular mechanisms underlying these morphological alterations remain largely unknown. Here, we found that miR-9-5p levels were selectively reduced in the hippocampus of rats vulnerable to Chronic Mild Stress (CMS), while acute subanesthetic ketamine restored its levels to basal condition in just 24h; miR-9-5p expression inversely correlated with the anhedonic phenotype. A decrease of miR-9-5p was reproduced in an in vitro model of stress, based on primary hippocampal neurons incubated with the stress hormone corticosterone. In both CMS animals and primary neurons, decreased miR-9-5p levels were associated with dendritic simplification, while treatment with ketamine completely rescued the changes. In vitro modulation of miR-9-5p expression showed a direct role of miR-9-5p in regulating dendritic length and spine density in mature primary hippocampal neurons. Among the putative target genes tested, Rest and Sirt1 were validated as biological targets in primary neuronal cultures. Moreover, in line with miR-9-5p changes, REST protein expression levels were remarkably increased in both CMS vulnerable animals and corticosterone-treated neurons, while ketamine completely abolished this alteration. Finally, the shortening of dendritic length in corticosterone-treated neurons was shown to be partly rescued by miR-9-5p overexpression and dependent on REST protein expression. Overall, our data unveiled the functional role of miR-9-5p in the remodeling of dendritic arbor induced by stress/corticosterone in vulnerable animals and its rescue by acute antidepressant treatment with ketamine.
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Affiliation(s)
- Jessica Mingardi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Luca La Via
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Paolo Tornese
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milano, Italy
| | - Giulia Carini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Kalevi Trontti
- Sleep Well Research Program, Department of Psychology and Logopedics, and Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Mara Seguini
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milano, Italy
| | - Daniela Tardito
- Department of Technical and Applied Sciences, eCampus University, Novedrate, Italy
| | - Federica Bono
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Chiara Fiorentini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Leonardo Elia
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- Humanitas Clinical and Research Center, IRCCS, Rozzano, MI, Italy
| | - Iiris Hovatta
- Sleep Well Research Program, Department of Psychology and Logopedics, and Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Maurizio Popoli
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milano, Italy
| | - Laura Musazzi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Alessandro Barbon
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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44
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Hansen KB, Wollmuth LP, Bowie D, Furukawa H, Menniti FS, Sobolevsky AI, Swanson GT, Swanger SA, Greger IH, Nakagawa T, McBain CJ, Jayaraman V, Low CM, Dell'Acqua ML, Diamond JS, Camp CR, Perszyk RE, Yuan H, Traynelis SF. Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels. Pharmacol Rev 2021; 73:298-487. [PMID: 34753794 PMCID: PMC8626789 DOI: 10.1124/pharmrev.120.000131] [Citation(s) in RCA: 372] [Impact Index Per Article: 93.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels are critical to brain function and are centrally implicated in numerous psychiatric and neurologic disorders. There are different classes of iGluRs with a variety of receptor subtypes in each class that play distinct roles in neuronal functions. The diversity in iGluR subtypes, with their unique functional properties and physiologic roles, has motivated a large number of studies. Our understanding of receptor subtypes has advanced considerably since the first iGluR subunit gene was cloned in 1989, and the research focus has expanded to encompass facets of biology that have been recently discovered and to exploit experimental paradigms made possible by technological advances. Here, we review insights from more than 3 decades of iGluR studies with an emphasis on the progress that has occurred in the past decade. We cover structure, function, pharmacology, roles in neurophysiology, and therapeutic implications for all classes of receptors assembled from the subunits encoded by the 18 ionotropic glutamate receptor genes. SIGNIFICANCE STATEMENT: Glutamate receptors play important roles in virtually all aspects of brain function and are either involved in mediating some clinical features of neurological disease or represent a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of this class of receptors will advance our understanding of many aspects of brain function at molecular, cellular, and system levels and provide new opportunities to treat patients.
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Affiliation(s)
- Kasper B Hansen
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Lonnie P Wollmuth
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Derek Bowie
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Hiro Furukawa
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Frank S Menniti
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Alexander I Sobolevsky
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Geoffrey T Swanson
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Sharon A Swanger
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Ingo H Greger
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Terunaga Nakagawa
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Chris J McBain
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Vasanthi Jayaraman
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Chian-Ming Low
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Mark L Dell'Acqua
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Jeffrey S Diamond
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Chad R Camp
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Riley E Perszyk
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Hongjie Yuan
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Stephen F Traynelis
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
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Aleksandrova LR, Phillips AG. Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends Pharmacol Sci 2021; 42:929-942. [PMID: 34565579 DOI: 10.1016/j.tips.2021.08.003] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/19/2021] [Accepted: 08/20/2021] [Indexed: 12/20/2022]
Abstract
The emerging therapeutic efficacy of ketamine and classical psychedelics for depression has inspired tremendous interest in the underlying neurobiological mechanisms. We review preclinical and clinical evidence supporting neuroplasticity as a convergent downstream mechanism of action for these novel fast-acting antidepressants. Through their primary glutamate or serotonin receptor targets, ketamine and psychedelics [psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT)] induce synaptic, structural, and functional changes, particularly in pyramidal neurons in the prefrontal cortex. These include increased glutamate release, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation, brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR)-mediated signaling, expression of synaptic proteins, and synaptogenesis. Such influences may facilitate adaptive rewiring of pathological neurocircuitry, thus providing a neuroplasticity-focused framework to explain the robust and sustained therapeutic effects of these compounds.
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Affiliation(s)
- Lily R Aleksandrova
- Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
| | - Anthony G Phillips
- Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
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46
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Lin PY, Ma ZZ, Mahgoub M, Kavalali ET, Monteggia LM. A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action. Cell Rep 2021; 36:109513. [PMID: 34407417 PMCID: PMC8404212 DOI: 10.1016/j.celrep.2021.109513] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 05/14/2021] [Accepted: 07/21/2021] [Indexed: 12/17/2022] Open
Abstract
Ketamine produces rapid antidepressant action in patients with major depression or treatment-resistant depression. Studies have identified brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), as necessary for the antidepressant effects and underlying ketamine-induced synaptic potentiation in the hippocampus. Here, we delete BDNF or TrkB in presynaptic CA3 or postsynaptic CA1 regions of the Schaffer collateral pathway to investigate the rapid antidepressant action of ketamine. The deletion of Bdnf in CA3 or CA1 blocks the ketamine-induced synaptic potentiation. In contrast, ablation of TrkB only in postsynaptic CA1 eliminates the ketamine-induced synaptic potentiation. We confirm BDNF-TrkB signaling in CA1 is required for ketamine's rapid behavioral action. Moreover, ketamine application elicits dynamin1-dependent TrkB activation and downstream signaling to trigger rapid synaptic effects. Taken together, these data demonstrate a requirement for BDNF-TrkB signaling in CA1 neurons in ketamine-induced synaptic potentiation and identify a specific synaptic locus in eliciting ketamine's rapid antidepressant effects.
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Affiliation(s)
- Pei-Yi Lin
- Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA; Department of Neuroscience, the University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA
| | - Z Zack Ma
- Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-2050, USA
| | - Melissa Mahgoub
- Department of Neuroscience, the University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA
| | - Ege T Kavalali
- Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-2050, USA
| | - Lisa M Monteggia
- Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-2050, USA.
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Colameo D, Rajman M, Soutschek M, Bicker S, von Ziegler L, Bohacek J, Winterer J, Germain PL, Dieterich C, Schratt G. Pervasive compartment-specific regulation of gene expression during homeostatic synaptic scaling. EMBO Rep 2021; 22:e52094. [PMID: 34396684 PMCID: PMC8490987 DOI: 10.15252/embr.202052094] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 07/12/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022] Open
Abstract
Synaptic scaling is a form of homeostatic plasticity which allows neurons to adjust their action potential firing rate in response to chronic alterations in neural activity. Synaptic scaling requires profound changes in gene expression, but the relative contribution of local and cell‐wide mechanisms is controversial. Here we perform a comprehensive multi‐omics characterization of the somatic and process compartments of primary rat hippocampal neurons during synaptic scaling. We uncover both highly compartment‐specific and correlating changes in the neuronal transcriptome and proteome. Whereas downregulation of crucial regulators of neuronal excitability occurs primarily in the somatic compartment, structural components of excitatory postsynapses are mostly downregulated in processes. Local inhibition of protein synthesis in processes during scaling is confirmed for candidate synaptic proteins. Motif analysis further suggests an important role for trans‐acting post‐transcriptional regulators, including RNA‐binding proteins and microRNAs, in the local regulation of the corresponding mRNAs. Altogether, our study indicates that, during synaptic scaling, compartmentalized gene expression changes might co‐exist with neuron‐wide mechanisms to allow synaptic computation and homeostasis.
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Affiliation(s)
- David Colameo
- Laboratory of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland.,Neuroscience Center Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland
| | - Marek Rajman
- Institute for Physiological Chemistry, Biochemical-Pharmacological Center Marburg, Philipps-University of Marburg, Marburg, Germany
| | - Michael Soutschek
- Laboratory of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland.,Neuroscience Center Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland
| | - Silvia Bicker
- Laboratory of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland.,Neuroscience Center Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland
| | - Lukas von Ziegler
- Neuroscience Center Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland.,Laboratory of Behavioural and Molecular Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland
| | - Johannes Bohacek
- Neuroscience Center Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland.,Laboratory of Behavioural and Molecular Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland
| | - Jochen Winterer
- Laboratory of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland.,Neuroscience Center Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland
| | - Pierre-Luc Germain
- Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland.,Laboratory of Statistical Bioinformatics, Department of Molecular Life Sciences, University of Zürich, Zurich, Switzerland
| | - Christoph Dieterich
- Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, Heidelberg, Germany
| | - Gerhard Schratt
- Laboratory of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland.,Neuroscience Center Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland
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Banerjee S, Vernon S, Jiao W, Choi BJ, Ruchti E, Asadzadeh J, Burri O, Stowers RS, McCabe BD. Miniature neurotransmission is required to maintain Drosophila synaptic structures during ageing. Nat Commun 2021; 12:4399. [PMID: 34285221 PMCID: PMC8292383 DOI: 10.1038/s41467-021-24490-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 06/22/2021] [Indexed: 11/27/2022] Open
Abstract
The decline of neuronal synapses is an established feature of ageing accompanied by the diminishment of neuronal function, and in the motor system at least, a reduction of behavioural capacity. Here, we have investigated Drosophila motor neuron synaptic terminals during ageing. We observed cumulative fragmentation of presynaptic structures accompanied by diminishment of both evoked and miniature neurotransmission occurring in tandem with reduced motor ability. Through discrete manipulation of each neurotransmission modality, we find that miniature but not evoked neurotransmission is required to maintain presynaptic architecture and that increasing miniature events can both preserve synaptic structures and prolong motor ability during ageing. Our results establish that miniature neurotransmission, formerly viewed as an epiphenomenon, is necessary for the long-term stability of synaptic connections. Synaptic structures disintegrate and fragment as ageing progresses. Here the authors find that miniature neurotransmission is required to maintain adult motor synapse structures in Drosophila and that increasing miniature events can preserve motor ability during ageing.
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Affiliation(s)
- Soumya Banerjee
- Brain Mind Institute, EPFL - Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland
| | - Samuel Vernon
- Brain Mind Institute, EPFL - Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland
| | - Wei Jiao
- Brain Mind Institute, EPFL - Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland
| | - Ben Jiwon Choi
- Department of Biology, New York University, New York, USA
| | - Evelyne Ruchti
- Brain Mind Institute, EPFL - Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland
| | - Jamshid Asadzadeh
- Brain Mind Institute, EPFL - Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland
| | - Olivier Burri
- Brain Mind Institute, EPFL - Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland
| | - R Steven Stowers
- Department of Cell Biology and Neuroscience, Montana State University, Bozeman, USA
| | - Brian D McCabe
- Brain Mind Institute, EPFL - Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland.
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Abstract
After participating in this activity, learners should be better able to:• Identify the effects of dysregulated opioid signalling in depression• Evaluate the use of opioid compounds and ketamine in patients with depression ABSTRACT: Major depressive disorder (MDD) remains one of the leading causes of disability and functional impairment worldwide. Current antidepressant therapeutics require weeks to months of treatment prior to the onset of clinical efficacy on depressed mood but remain ineffective in treating suicidal ideation and cognitive impairment. Moreover, 30%-40% of individuals fail to respond to currently available antidepressant medications. MDD is a heterogeneous disorder with an unknown etiology; novel strategies must be developed to treat MDD more effectively. Emerging evidence suggests that targeting one or more of the four opioid receptors-mu (MOR), kappa (KOR), delta (DOR), and the nociceptin/orphanin FQ receptor (NOP)-may yield effective therapeutics for stress-related psychiatric disorders. Furthermore, the effects of the rapidly acting antidepressant ketamine may involve opioid receptors. This review highlights dysregulated opioid signaling in depression, evaluates clinical trials with opioid compounds, and considers the role of opioid mechanisms in rapidly acting antidepressants.
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50
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Rana T, Behl T, Sehgal A, Mehta V, Singh S, Sharma N, Bungau S. Elucidating the Possible Role of FoxO in Depression. Neurochem Res 2021; 46:2761-2775. [PMID: 34075521 DOI: 10.1007/s11064-021-03364-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/23/2021] [Accepted: 05/25/2021] [Indexed: 12/21/2022]
Abstract
Forkhead box-O (FoxO) transcriptional factors perform essential functions in several physiological and biological processes. Recent studies have shown that FoxO is implicated in the pathophysiology of depression. Changes in the upstream mediators of FoxOs including brain-derived neurotrophic factor (BDNF) and protein kinase B have been associated with depressive disorder and the antidepressant agents are known to alter the phosphorylation of FoxOs. Moreover, FoxOs might be regulated by serotonin or noradrenaline signaling and the hypothalamic-pituitary-adrenal (HPA)-axis,both of them are associated with the development of the depressive disorder. FoxO also regulates neural morphology, synaptogenesis, and neurogenesis in the hippocampus, which accounts for the pathogenesis of the depressive disorder. The current article underlined the potential functions of FoxOs in the etiology of depressive disorder and formulate few essential proposals for further investigation. The review also proposes that FoxO and its signal pathway might establish possible therapeutic mediators for the management of depressive disorder.
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Affiliation(s)
- Tarapati Rana
- Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India.,Government Pharmacy College, Seraj, Mandi, Himachal Pradesh, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India
| | - Vineet Mehta
- Government College of Pharmacy, Rohru, Distt., Shimla, Himachal Pradesh, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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