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Anderson MC, Crespo-Garcia M, Subbulakshmi S. Brain mechanisms underlying the inhibitory control of thought. Nat Rev Neurosci 2025:10.1038/s41583-025-00929-y. [PMID: 40379896 DOI: 10.1038/s41583-025-00929-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2025] [Indexed: 05/19/2025]
Abstract
Controlling action and thought requires the capacity to stop mental processes. Over the past two decades, evidence has grown that a domain-general inhibitory control mechanism supported by the right lateral prefrontal cortex achieves these functions. However, current views of the neural mechanisms of inhibitory control derive largely from research into the stopping of action. Whereas action stopping is a convenient empirical model, it does not invoke thought inhibition and cannot be used to identify the unique features of this process. Here, we review research that addresses how organisms stop a key process that drives thoughts: memory retrieval. This work has shown that retrieval stopping shares right dorsolateral and ventrolateral prefrontal mechanisms with action stopping, consistent with a domain-general inhibitory control mechanism, but also recruits a distinct fronto-temporal pathway that determines the success of mental control. As part of this pathway, GABAergic inhibition within the hippocampus influences the efficacy of prefrontal control over thought. These unique elements of mental control suggest that hippocampal disinhibition is a transdiagnostic factor underlying intrusive thinking, linking the fronto-temporal control pathway to preclinical models of psychiatric disorders and fear extinction. We suggest that retrieval-stopping deficits may underlie the intrusive thinking that is common across many psychiatric disorders.
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Affiliation(s)
- Michael C Anderson
- MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.
- Behavioural and Clinical Neurosciences Unit, University of Cambridge, Cambridge, UK.
| | - Maite Crespo-Garcia
- MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK
| | - S Subbulakshmi
- Department of Psychology, Stanford University, Stanford, CA, USA
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2
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Pakkhesal S, Shakouri M, Mosaddeghi-Heris R, Kiani Nasab S, Salehi N, Sharafi A, Ahmadalipour A. Bridging the gap: The endocannabinoid system as a functional fulcrum for benzodiazepines in a novel frontier of anxiety pharmacotherapy. Pharmacol Ther 2025; 267:108799. [PMID: 39862927 DOI: 10.1016/j.pharmthera.2025.108799] [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: 05/21/2024] [Revised: 09/27/2024] [Accepted: 01/18/2025] [Indexed: 01/27/2025]
Abstract
While benzodiazepines have been a mainstay of the pharmacotherapy of anxiety disorders, their short-term efficacy and risk of abuse have driven the exploration of alternative treatment approaches. The endocannabinoid (eCB) system has emerged as a key modulator of anxiety-related processes, with evidence suggesting dynamic interactions between the eCB system and the GABAergic system, the primary target of benzodiazepines. According to the existing literature, the activation of the cannabinoid receptors has been shown to exert anxiolytic effects, while their blockade or genetic deletion results in heightened anxiety-like responses. Moreover, studies have provided evidence of interactions between the eCB system and benzodiazepines in anxiety modulation. For instance, the attenuation of benzodiazepine-induced anxiolysis by cannabinoid receptor antagonism or genetic variations in the eCB system components in animal studies, have been associated with variations in benzodiazepine response and susceptibility to anxiety disorders. The combined use of cannabinoid-based medications, such as cannabinoid receptor agonists and benzodiazepine co-administration, has shown promise in augmenting anxiolytic effects and reducing benzodiazepine dosage requirements. This article aims to comprehensively review and discuss the current evidence on the involvement of the eCB system as a key modulator of benzodiazepine-related anxiolytic effects, and further, the possible mechanisms by which the region-specific eCB system-GABAergic connectivity modulates the neuro-endocrine/behavioral stress response, providing an inclusive understanding of the complex interplay between the eCB system and benzodiazepines in the context of anxiety regulation, to inform future research and clinical practice.
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Affiliation(s)
- Sina Pakkhesal
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Shakouri
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Mosaddeghi-Heris
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Kiani Nasab
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Negin Salehi
- Student Research Committee, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - AmirMohammad Sharafi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Faculty of Pharmacy, Tabriz University of Medical Sciences, 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; Department of Biomedical Engineering, The City College of New York, New York, NY, USA.
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Chen G, Xu M, Chen Z, Yang F. Clinical applications of small-molecule GABA AR modulators for neurological disorders. Bioorg Chem 2024; 153:107983. [PMID: 39581171 DOI: 10.1016/j.bioorg.2024.107983] [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: 10/02/2024] [Revised: 10/31/2024] [Accepted: 11/17/2024] [Indexed: 11/26/2024]
Abstract
Gamma-aminobutyric acid type A receptor (GABAAR) modulators are crucial in treating neurological and psychiatric disorders, including epilepsy, anxiety, insomnia, and depression. This review examines the synthetic approaches and clinical applications of representative small-molecule GABAAR modulators. Benzodiazepines, such as Diazepam, are well-known positive allosteric modulators (PAMs) that enhance GABAAR function, providing therapeutic effects but also associated with side effects like sedation and dependence. Non-benzodiazepine modulators, including Z-drugs like Zolpidem and Zaleplon, offer improved selectivity for the α1 subunit of GABAAR, reducing some of these side effects. Neurosteroids such as allopregnanolone and its synthetic analogs, including Brexanolone, have emerged as potent GABAAR modulators with applications in conditions like postpartum depression and refractory epilepsy. Advances in molecular biology and pharmacology have facilitated the development of isoform-specific modulators, potentially reducing off-target effects and enhancing therapeutic profiles. Additionally, combining GABAAR modulators with other therapeutic agents has shown promise in enhancing efficacy and minimizing side effects. This review highlights the design strategies, pharmacodynamics, clinical efficacy, and safety profiles of these compounds, emphasizing the opportunities for developing novel GABAAR modulators with improved therapeutic outcomes.
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Affiliation(s)
- Guangyong Chen
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Meiling Xu
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhuo Chen
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, China.
| | - Fuwei Yang
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, China.
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Qiao J, Tao S, Sun Y, Shi J, Chen Y, Tian S, Yao Z, Lu Q. The Effects of Variation in the GABA A Receptor Gene on Anxious Depression are Mediated by the Functional Connectivity Between the Amygdala and Middle Frontal Gyrus. Neuropsychiatr Dis Treat 2024; 20:1781-1796. [PMID: 39346029 PMCID: PMC11438461 DOI: 10.2147/ndt.s468290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024] Open
Abstract
Background γ-aminobutyric acid (GABA) and its main receptor, the GABAA receptor, are implicated in major depressive disorder (MDD). Anxious depression (AD) is deemed to be a primary subtype of MDD. The amygdala and the dorsolateral prefrontal cortex (DLPFC) are key brain regions involved in emotional regulation. These regions contain the most GABAA receptors. Although the GABAergic deficit hypothesis of MDD is generally accepted, few studies have demonstrated how GABAA receptor gene polymorphisms affect the functions of specific brain regions, in particular, the amygdala and the DLPFC. Methods The sample comprised 83 patients with AD, 70 patients with non-anxious depression (NAD), and 62 healthy controls (HC). All participants underwent genotyping for polymorphisms of GABAA receptor subunit genes, followed by a resting-state fMRI scan. The HAMD-17 was used to evaluate the severity of MDD. ANOVA was performed to obtain the difference in the imaging data, GABAA receptor multi-locus genetic profile scores (MGPS), and HAMD-17 scores among three groups, then the significant differences between AD and NAD groups were identified. Mediating effect analysis was used to explore the role of functional connectivity (FC) between the amygdala and DLPFC in the association between the GABAA receptor gene MGPS and AD clinical features. Results Compared with the NAD group, the AD group had a higher GABAA receptor MGPS. AD patients exhibited a negative correlation between the MGPS and FC of the right centromedial (CM) subregion, and the right middle frontal gyrus (MFG). A negative correlation was also observed between the MGPS and anxiety/somatic symptoms. More importantly, the right CM and right MFG connectivity mediated the association between the GABAA receptor MGPS and anxiety/somatic symptoms in patients with AD. Conclusion The decreased FC between the right MFG and right CM subregion mediates the association between GABAA receptor MGPS and AD.
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Affiliation(s)
- Juan Qiao
- Department of Psychology, Xuzhou East Hospital Affiliated to Xuzhou Medical University, Xuzhou, People’s Republic of China
- Department of Psychiatry, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, People’s Republic of China
| | - Shiwan Tao
- Department of Psychiatry, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yurong Sun
- School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, People’s Republic of China
- Key Laboratory of Child Development and Learning Science, Ministry of Education, Nanjing, People’s Republic of China
| | - Jiabo Shi
- Department of Psychiatry, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, People’s Republic of China
- Nanjing Brain Hospital, School of Medicine, Nanjing University, Nanjing, People’s Republic of China
| | - Yu Chen
- Department of Psychiatry, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, People’s Republic of China
- Nanjing Brain Hospital, School of Medicine, Nanjing University, Nanjing, People’s Republic of China
| | - Shui Tian
- School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, People’s Republic of China
- Key Laboratory of Child Development and Learning Science, Ministry of Education, Nanjing, People’s Republic of China
| | - Zhijian Yao
- Department of Psychiatry, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, People’s Republic of China
- Nanjing Brain Hospital, School of Medicine, Nanjing University, Nanjing, People’s Republic of China
| | - Qing Lu
- School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, People’s Republic of China
- Key Laboratory of Child Development and Learning Science, Ministry of Education, Nanjing, People’s Republic of China
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Luscher B, Jiang T, Feng M, Hutsell A. Sex-specific GABAergic microcircuits that switch vulnerability into resilience to stress and reverse the effects of chronic stress exposure. RESEARCH SQUARE 2024:rs.3.rs-4408723. [PMID: 39041032 PMCID: PMC11261964 DOI: 10.21203/rs.3.rs-4408723/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
Clinical and preclinical studies have identified somatostatin (SST)-positive interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, disinhibition of SST neurons in mice results in resilience to the behavioral effects of chronic stress. Here we established a low-dose chronic chemogenetic protocol to map these changes in positively and negatively motivated behaviors to specific brain regions. AAV-hM3Dq mediated chronic activation of SST neurons in the prelimbic cortex (PLC) had antidepressant drug-like effects on anxiety- and anhedonia-related motivated behaviors in male but not female mice. Analogous manipulation of the ventral hippocampus (vHPC) had such effects in female but not male mice. Moreover, activation of SST neurons in the PLC of male and the vHPC of female mice resulted in stress resilience. Activation of SST neurons in the PLC reversed prior chronic stress-induced defects in motivated behavior in males but was ineffective in females. Conversely, activation of SST neurons in the vHPC reversed chronic stress-induced behavioral alterations in females but not males. Quantitation of c-Fos+ and FosB+ neurons in chronic stress-exposed mice revealed that chronic activation of SST neurons leads to a paradoxical increase in pyramidal cell activity. Collectively, these data demonstrate that GABAergic microcircuits driven by dendrite targeting interneurons enable sex- and brain-region-specific neural plasticity that promotes stress resilience and reverses stress-induced anxiety- and anhedonia-like motivated behavior. Our studies provide a mechanistic rationale for antidepressant efficacy of dendrite-targeting, low-potency GABAA receptor agonists, independent of sex and despite striking sex differences in the relevant brain substrates.
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Jellinger AL, Suthard RL, Yuan B, Surets M, Ruesch EA, Caban AJ, Liu S, Shpokayte M, Ramirez S. Chronic activation of a negative engram induces behavioral and cellular abnormalities. eLife 2024; 13:RP96281. [PMID: 38990919 PMCID: PMC11239178 DOI: 10.7554/elife.96281] [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] [Indexed: 07/13/2024] Open
Abstract
Negative memories engage a brain and body-wide stress response in humans that can alter cognition and behavior. Prolonged stress responses induce maladaptive cellular, circuit, and systems-level changes that can lead to pathological brain states and corresponding disorders in which mood and memory are affected. However, it is unclear if repeated activation of cells processing negative memories induces similar phenotypes in mice. In this study, we used an activity-dependent tagging method to access neuronal ensembles and assess their molecular characteristics. Sequencing memory engrams in mice revealed that positive (male-to-female exposure) and negative (foot shock) cells upregulated genes linked to anti- and pro-inflammatory responses, respectively. To investigate the impact of persistent activation of negative engrams, we chemogenetically activated them in the ventral hippocampus over 3 months and conducted anxiety and memory-related tests. Negative engram activation increased anxiety behaviors in both 6- and 14-month-old mice, reduced spatial working memory in older mice, impaired fear extinction in younger mice, and heightened fear generalization in both age groups. Immunohistochemistry revealed changes in microglial and astrocytic structure and number in the hippocampus. In summary, repeated activation of negative memories induces lasting cellular and behavioral abnormalities in mice, offering insights into the negative effects of chronic negative thinking-like behaviors on human health.
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Affiliation(s)
- Alexandra L Jellinger
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
| | - Rebecca L Suthard
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
- Graduate Program for Neuroscience, Boston University, Boston, United States
| | - Bingbing Yuan
- Whitehead Institute for Biomedical Research, MIT, Cambridge, United States
| | - Michelle Surets
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
| | - Evan A Ruesch
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
| | - Albit J Caban
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
- Graduate Program for Neuroscience, Boston University, Boston, United States
| | - Shawn Liu
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
| | - Monika Shpokayte
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
- Graduate Program for Neuroscience, Boston University, Boston, United States
| | - Steve Ramirez
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
- Neurophotonics Center, and Photonics Center, Boston University, Boston, United States
- Department of Biomedical Engineering, Boston University, Boston, United States
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Poliquin S, Nwosu G, Randhave K, Shen W, Flamm C, Kang JQ. Modulating Endoplasmic Reticulum Chaperones and Mutant Protein Degradation in GABRG2(Q390X) Associated with Genetic Epilepsy with Febrile Seizures Plus and Dravet Syndrome. Int J Mol Sci 2024; 25:4601. [PMID: 38731820 PMCID: PMC11083348 DOI: 10.3390/ijms25094601] [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: 03/04/2024] [Revised: 04/10/2024] [Accepted: 04/17/2024] [Indexed: 05/13/2024] Open
Abstract
A significant number of patients with genetic epilepsy do not obtain seizure freedom, despite developments in new antiseizure drugs, suggesting a need for novel therapeutic approaches. Many genetic epilepsies are associated with misfolded mutant proteins, including GABRG2(Q390X)-associated Dravet syndrome, which we have previously shown to result in intracellular accumulation of mutant GABAA receptor γ2(Q390X) subunit protein. Thus, a potentially promising therapeutic approach is modulation of proteostasis, such as increasing endoplasmic reticulum (ER)-associated degradation (ERAD). To that end, we have here identified an ERAD-associated E3 ubiquitin ligase, HRD1, among other ubiquitin ligases, as a strong modulator of wildtype and mutant γ2 subunit expression. Overexpressing HRD1 or knockdown of HRD1 dose-dependently reduced the γ2(Q390X) subunit. Additionally, we show that zonisamide (ZNS)-an antiseizure drug reported to upregulate HRD1-reduces seizures in the Gabrg2+/Q390X mouse. We propose that a possible mechanism for this effect is a partial rescue of surface trafficking of GABAA receptors, which are otherwise sequestered in the ER due to the dominant-negative effect of the γ2(Q390X) subunit. Furthermore, this partial rescue was not due to changes in ER chaperones BiP and calnexin, as total expression of these chaperones was unchanged in γ2(Q390X) models. Our results here suggest that leveraging the endogenous ERAD pathway may present a potential method to degrade neurotoxic mutant proteins like the γ2(Q390X) subunit. We also demonstrate a pharmacological means of regulating proteostasis, as ZNS alters protein trafficking, providing further support for the use of proteostasis regulators for the treatment of genetic epilepsies.
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Affiliation(s)
- Sarah Poliquin
- Neuroscience Graduate Program, Vanderbilt University, Nashville, TN 37232, USA;
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA;
| | - Gerald Nwosu
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA;
- Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA
- Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave South, Nashville, TN 37232, USA; (K.R.); (W.S.); (C.F.)
| | - Karishma Randhave
- Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave South, Nashville, TN 37232, USA; (K.R.); (W.S.); (C.F.)
| | - Wangzhen Shen
- Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave South, Nashville, TN 37232, USA; (K.R.); (W.S.); (C.F.)
| | - Carson Flamm
- Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave South, Nashville, TN 37232, USA; (K.R.); (W.S.); (C.F.)
| | - Jing-Qiong Kang
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA;
- Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave South, Nashville, TN 37232, USA; (K.R.); (W.S.); (C.F.)
- Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt Kennedy Center of Human Development, Vanderbilt University, Nashville, TN 37232, USA
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Gharibi S, Vaillend C, Lindsay A. The unconditioned fear response in vertebrates deficient in dystrophin. Prog Neurobiol 2024; 235:102590. [PMID: 38484964 DOI: 10.1016/j.pneurobio.2024.102590] [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: 09/28/2023] [Revised: 01/31/2024] [Accepted: 03/05/2024] [Indexed: 03/19/2024]
Abstract
Dystrophin loss due to mutations in the Duchenne muscular dystrophy (DMD) gene is associated with a wide spectrum of neurocognitive comorbidities, including an aberrant unconditioned fear response to stressful/threat stimuli. Dystrophin-deficient animal models of DMD demonstrate enhanced stress reactivity that manifests as sustained periods of immobility. When the threat is repetitive or severe in nature, dystrophinopathy phenotypes can be exacerbated and even cause sudden death. Thus, it is apparent that enhanced sensitivity to stressful/threat stimuli in dystrophin-deficient vertebrates is a legitimate cause of concern for patients with DMD that could impact neurocognition and pathophysiology. This review discusses our current understanding of the mechanisms and consequences of the hypersensitive fear response in preclinical models of DMD and the potential challenges facing clinical translatability.
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Affiliation(s)
- Saba Gharibi
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
| | - Cyrille Vaillend
- Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, Saclay 91400, France.
| | - Angus Lindsay
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia; School of Biological Sciences, University of Canterbury, Christchurch 8041, New Zealand; Department of Medicine, University of Otago, Christchurch 8014, New Zealand.
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Wu H, Yue C, Cao F, Long Y, Wang Y. Self-processing characteristics from first-person and third-person perspectives in individuals with social anxiety disorder: insights into negative bias. Front Psychiatry 2024; 14:1283624. [PMID: 38375515 PMCID: PMC10875139 DOI: 10.3389/fpsyt.2023.1283624] [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: 08/26/2023] [Accepted: 12/26/2023] [Indexed: 02/21/2024] Open
Abstract
Background As one of the most common psychological problems, social anxiety disorder (SAD) has lots of negative effects on the physical and mental development of individuals, such as decreasing the quality of interpersonal relationships, and even causing depression, suicidal ideation, etc., as well as leads individuals to generate mental illness stigma. The mental illness stigma that individuals perceive affects not only how they perceive themselves (first-person perspective) but also how they perceive others' appraisals of them (third-person perspective), which further exacerbates their anxiety symptoms. Objective The study aims to explore the self-processing characteristics of individuals with social anxiety disorder from the first-person perspective and the third-person perspective. Methods This study adopted the self-referential paradigm to conduct the recognition memory test on individuals with social anxiety disorder (30 participants in experiment 1) and individuals without social anxiety disorder (31 participants in experiment 2) in the two experiments. Results In experiment 1, the recognition rate of individuals with social anxiety disorder under the self-appraisals condition was significantly higher than that under the condition of appraisals on mothers; in the three conditions of self-appraisals, appraisals on mothers and mothers' reflected appraisals, the recognition rate of negative trait adjectives was significantly higher than that of positive trait adjectives. In experiment 2, there was no significant difference in recognition rate of individuals without social anxiety disorder under the three conditions, and the recognition rate of positive trait adjectives was significantly higher than that of negative trait adjectives under the three conditions. Conclusion Individuals with social anxiety disorder have a negative bias in self-processing and are more likely to focus on self-information, which is different from the self-positive bias of individuals without social anxiety disorder. This study can be beneficial to know the self-cognitive characteristics of individuals with social anxiety disorder, help them get rid of negative cognitive patterns, and remove the mental illness stigma.
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Affiliation(s)
- Huating Wu
- College of National Culture and Cognitive Science, Guizhou Minzu University, Guiyang, China
| | - Caizhen Yue
- College of National Culture and Cognitive Science, Guizhou Minzu University, Guiyang, China
| | - Fasheng Cao
- College of National Culture and Cognitive Science, Guizhou Minzu University, Guiyang, China
| | - Yihong Long
- College of National Culture and Cognitive Science, Guizhou Minzu University, Guiyang, China
- School of Public Administration, South China University of Technology, Guangzhou, China
| | - Yan Wang
- The Faculty of Education, Southwest University, Chongqing, China
- International Affairs Office, Chongqing University of Arts and Sciences, Chongqing, China
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Shen W, Flamm C, Delahanty AJ, Casteel E, Biven M, DeLeeuw MB, Poliquin S, Nwosu G, Randhave K, Kang JQ. 4-Phenylbutyrate promoted wild-type γ-aminobutyric acid type A receptor trafficking, reduced endoplasmic reticulum stress, and mitigated seizures in Gabrg2 +/Q390X mice associated with Dravet syndrome. Epilepsia 2024; 65:204-217. [PMID: 37746768 PMCID: PMC10842976 DOI: 10.1111/epi.17779] [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: 04/10/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 09/26/2023]
Abstract
OBJECTIVE γ-Aminobutyric acid type A (GABAA ) receptor subunit gene mutations are major causes of various epilepsy syndromes, including severe kinds such as Dravet syndrome. Although the GABAA receptor is a major target for antiseizure medications, treating GABAA receptor mutations with receptor channel modulators is ineffective. Here, we determined the effect of a novel treatment with 4-phenylbutyrate (PBA) in Gabrg2+/Q390X knockin mice associated with Dravet syndrome. METHODS We used biochemistry in conjunction with differential tagging of the wild-type and the mutant alleles, live brain slice surface biotinylation, microsome isolation, patch-clamp whole-cell recordings, and video-monitoring synchronized electroencephalographic (EEG) recordings in Gabrg2+/Q390X mice to determine the effect of PBA in vitro with recombinant GABAA receptors and in vivo with knockin mice. RESULTS We found that PBA reduced the mutant γ2(Q390X) subunit protein aggregates, enhanced the wild-type GABAA receptor subunits' trafficking, and increased the membrane expression of the wild-type receptors. PBA increased the current amplitude of GABA-evoked current in human embryonic kidney 293T cells and the neurons bearing the γ2(Q390X) subunit protein. PBA also proved to reduce endoplasmic reticulum (ER) stress caused by the mutant γ2(Q390X) subunit protein, as well as mitigating seizures and EEG abnormalities in the Gabrg2+/Q390X mice. SIGNIFICANCE This research has unveiled a promising and innovative approach for treating epilepsy linked to GABAA receptor mutations through an unconventional antiseizure mechanism. Rather than directly modulating the affected mutant channel, PBA facilitates the folding and transportation of wild-type receptor subunits to the cell membrane and synapse. Combining these findings with our previous study, which demonstrated PBA's efficacy in restoring GABA transporter 1 (encoded by SLC6A1) function, we propose that PBA holds significant potential for a wide range of genetic epilepsies. Its ability to target shared molecular pathways involving mutant protein ER retention and impaired protein membrane trafficking suggests broad application in treating such conditions.
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Affiliation(s)
- Wangzhen Shen
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN
| | - Carson Flamm
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN
| | - Aiden J Delahanty
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN
| | - Emmett Casteel
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN
| | - Marshall Biven
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN
| | - Melissa B DeLeeuw
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Sarah Poliquin
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN
| | - Gerald Nwosu
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Karishma Randhave
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN
| | - Jing-Qiong Kang
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN
- the Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN
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11
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Jiang J, Tan S, Feng X, Peng Y, Long C, Yang L. Distinct ACC Neural Mechanisms Underlie Authentic and Transmitted Anxiety Induced by Maternal Separation in Mice. J Neurosci 2023; 43:8201-8218. [PMID: 37845036 PMCID: PMC10697407 DOI: 10.1523/jneurosci.0558-23.2023] [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: 03/27/2023] [Revised: 09/07/2023] [Accepted: 09/13/2023] [Indexed: 10/18/2023] Open
Abstract
It is known that humans and rodents are capable of transmitting stress to their naive partners via social interaction. However, a comprehensive understanding of transmitted stress, which may differ from authentic stress, thus revealing unique neural mechanisms of social interaction resulting from transmitted stress and the associated anxiety, is missing. We used, in the present study, maternal separation (MS) as a stress model to investigate whether MS causes abnormal behavior in adolescence. A key concern in the analysis of stress transmission is whether the littermates of MS mice who only witness MS stress ("Partners") exhibit behavioral abnormalities similar to those of MS mice themselves. Of special interest is the establishment of the neural mechanisms underlying transmitted stress and authentic stress. The results show that Partners, similar to MS mice, exhibit anxiety-like behavior and hyperalgesia after witnessing littermates being subjected to early-life repetitive MS. Electrophysiological analysis revealed that mice subjected to MS demonstrate a reduction in both the excitatory and inhibitory synaptic activities of parvalbumin interneurons (PVINs) in the anterior cingulate cortex (ACC). However, Partners differed from MS mice in showing an increase in the number and excitability of GABAergic PVINs in the ACC and in the ability of chemogenetic PVIN inactivation to eliminate abnormal behavior. Furthermore, the social transfer of anxiety-like behavior required intact olfactory, but not visual, perception. This study suggests a functional involvement of ACC PVINs in mediating the distinct neural basis of transmitted anxiety.SIGNIFICANCE STATEMENT The anterior cingulate cortex (ACC) is a critical brain area in physical and social pain and contributes to the exhibition of abnormal behavior. ACC glutamatergic neurons have been shown to encode transmitted stress, but it remains unclear whether inhibitory ACC neurons also play a role. We evaluate, in this study, ACC neuronal, synaptic and network activities and uncover a critical role of parvalbumin interneurons (PVINs) in the expression of transmitted stress in adolescent mice who had witnessed MS of littermates in infancy. Furthermore, inactivation of ACC PVINs blocks transmitted stress. The results suggest that emotional contagion has a severe effect on brain function, and identify a potential target for the treatment of transmitted anxiety.
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Affiliation(s)
- Jinxiang Jiang
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China
- School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Shuyi Tan
- School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Xiaoyi Feng
- School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Yigang Peng
- School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Cheng Long
- School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Li Yang
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China
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12
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Olah SS, Kareemo DJ, Buchta WC, Sinnen BL, Miller CN, Actor-Engel HS, Gookin SE, Winborn CS, Kleinjan MS, Crosby KC, Aoto J, Smith KR, Kennedy MJ. Acute reorganization of postsynaptic GABA A receptors reveals the functional impact of molecular nanoarchitecture at inhibitory synapses. Cell Rep 2023; 42:113331. [PMID: 37910506 PMCID: PMC10782565 DOI: 10.1016/j.celrep.2023.113331] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 09/01/2023] [Accepted: 10/06/2023] [Indexed: 11/03/2023] Open
Abstract
Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter release sites. While spatial coordination between pre- and postsynaptic elements is observed at both excitatory and inhibitory synapses, the functional significance of this molecular architecture has been challenging to evaluate experimentally. Here we utilized an optogenetic clustering approach to acutely alter the nanoscale organization of the postsynaptic inhibitory scaffold gephyrin while monitoring synaptic function. Gephyrin clustering rapidly enlarged postsynaptic area, laterally displacing GABAA receptors from their normally precise apposition with presynaptic active zones. Receptor displacement was accompanied by decreased synaptic GABAA receptor currents even though presynaptic release probability and the overall abundance and function of synaptic GABAA receptors remained unperturbed. Thus, acutely repositioning neurotransmitter receptors within the postsynaptic membrane profoundly influences synaptic efficacy, establishing the functional importance of precision pre-/postsynaptic molecular coordination at inhibitory synapses.
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Affiliation(s)
- Samantha S Olah
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Dean J Kareemo
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - William C Buchta
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Brooke L Sinnen
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Carley N Miller
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Hannah S Actor-Engel
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Sara E Gookin
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Christina S Winborn
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Mason S Kleinjan
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Kevin C Crosby
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Jason Aoto
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Katharine R Smith
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Matthew J Kennedy
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
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13
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Yu X, Gao Z, Gao M, Qiao M. Bibliometric Analysis on GABA-A Receptors Research Based on CiteSpace and VOSviewer. J Pain Res 2023; 16:2101-2114. [PMID: 37361426 PMCID: PMC10289248 DOI: 10.2147/jpr.s409380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/11/2023] [Indexed: 06/28/2023] Open
Abstract
Background GABA-A receptors are the primary mediators of brain inhibitory neurotransmission. In the past years, many studies focused on this channel to decipher the pathogenesis of related diseases but lacked bibliometric analysis research. This study aims to explore the research status and identify the research trends of GABA-A receptor channels. Methods Publications related to GABA-A receptor channels were retrieved from the Web of Science Core Collection from 2012 to 2022. After screening, the VOSviewer 1.6.18 and Citespace 5.8 R3 were used for bibliometric analysis from journals, countries, institutions, authors, co-cited references and keywords. Results We included 12,124 publications in the field of GABA-A receptor channels for analysis. The data shows that although there was a slight decrease in annual publications from 2012 to 2021, it remained at a relatively high level. Most publications were in the domain of neuroscience. Additionally, the United States was the most prolific country, followed by China. Univ Toronto was the most productive institution, and James M Cook led essential findings in this field. Furthermore, brain activation, GABAAR subunits expression, modulation mechanism in pain and anxiety behaviors and GABA and dopamine were paid attention to by researchers. And top research frontiers were molecular docking, autoimmune encephalitic series, obesity, sex difference, diagnosis and management, EEG and KCC2. Conclusion Taken together, academic attention on GABA-A receptor channels was never neglected since 2012. Our analysis identified key information, such as core countries, institutions and authors in this field. Molecular docking, autoimmune encephalitic series, obesity, sex difference, diagnosis and management, EEG and KCC2 will be the future research direction.
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Affiliation(s)
- Xufeng Yu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China
| | - Zhan Gao
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China
| | - Mingzhou Gao
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China
| | - Mingqi Qiao
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China
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14
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Zhang H, Gao Z, Sun Y, Lu T, Wang Z, Gao D, Wang J, Qiao M, Gao M. Profiling GABA(A) Receptor Subunit Expression in the Hippocampus of PMDD Rat Models Based on TCM Theories. Mol Neurobiol 2023:10.1007/s12035-023-03354-3. [PMID: 37103685 DOI: 10.1007/s12035-023-03354-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 04/15/2023] [Indexed: 04/28/2023]
Abstract
γ-Aminobutyric acid type A receptors (GABAARs) play an important role in cognitive and emotional regulation and are related to the hippocampus. However, little is known regarding patterns of hippocampal GABAAR subunit expression in rat models of premenstrual dysphoric disorder (PMDD). This study investigated the above changes by establishing two PMDD rat models based on Traditional Chinese Medicine (TCM) theories, namely, PMDD liver-qi invasion syndrome (PMDD-LIS) and PMDD liver-qi depression syndrome (PMDD-LDS). Behavioral tests were used to detect depression and irritability emotion. Western blot analysis was used to investigate protein levels of GABAAR α1, α2, α4, α5, β2, β3, and δ subunits, whereas ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis was performed to determine gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the hippocampus across each group. Concurrently, behavioral data indicated that the PMDD-LDS and PMDD-LIS rat models had been successfully established. GABAAR α2, α5, β2, and δ subunit was significantly upregulated, whereas α4 was significantly downregulated (P < 0.05) in PMDD-LDS rat models relative to controls. On the other hand, GABAAR α1, α2, and β3 were significantly downregulated while α4 and β2 were significantly upregulated in PMDD-LIS rat models relative to the control group (P < 0.05). Moreover, GABA levels significantly decreased, while Glu and the ratio of glutamate to GABA increased in PMDD-LIS rat models (P < 0.05). Conversely, GABA and Glu levels significantly decreased, whereas the ratio of glutamate to GABA increased in PMDD-LIS rat models (P < 0.05). Conclusively, our results revealed differential expression of GABAAR α1, α2, α4, α5, β2, β3, and δ subunits between PMDD-LIS and PMDD-LDS rat models, suggesting that they may be biomarkers in the pathogenesis of PMDD.
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Affiliation(s)
- Hao Zhang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Zhan Gao
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Ya Sun
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Tian Lu
- International Exchange and Cooperation Office, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Zhenzhen Wang
- Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Dongmei Gao
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Jieqiong Wang
- Office of Academic Research, Shandong University of Traditional Chinese Medicine, Jinan , Shandong Province, China
| | - Mingqi Qiao
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Mingzhou Gao
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China.
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15
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Shin HS, Lee SH, Moon HJ, So YH, Lee HR, Lee EH, Jung EM. Exposure to polystyrene particles causes anxiety-, depression-like behavior and abnormal social behavior in mice. JOURNAL OF HAZARDOUS MATERIALS 2023; 454:131465. [PMID: 37130475 DOI: 10.1016/j.jhazmat.2023.131465] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/04/2023] [Accepted: 04/20/2023] [Indexed: 05/04/2023]
Abstract
In the era of plastic use, organisms are constantly exposed to polystyrene particles (PS-Ps). PS-Ps accumulated in living organisms exert negative effects on the body, although studies evaluating their effects on brain development are scarce. In this study, the effects of PS-Ps on nervous system development were investigated using cultured primary cortical neurons and mice exposed to PS-Ps at different stages of brain development. The gene expression associated with brain development was downregulated in embryonic brains following PS-Ps exposure, and Gabra2 expression decreased in the embryonic and adult mice exposed to PS-Ps. Additionally, offspring of PS-Ps-treated dams exhibited signs of anxiety- and depression-like behavior, and abnormal social behavior. We propose that PS-Ps accumulation in the brain disrupts brain development and behavior in mice. This study provides novel information regarding PS-Ps toxicity and its harmful effects on neural development and behavior in mammals.
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Affiliation(s)
- Hyun Seung Shin
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Seung Hyun Lee
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Ha Jung Moon
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Yun Hee So
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Ha Ram Lee
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Eun-Hee Lee
- Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Eui-Man Jung
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea.
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16
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Automated Synthesis of [18F]Flumazenil Application in GABAA Receptor Neuroimaging Availability for Rat Model of Anxiety. Pharmaceuticals (Basel) 2023; 16:ph16030417. [PMID: 36986516 PMCID: PMC10058208 DOI: 10.3390/ph16030417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/03/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Clinical studies have demonstrated that the γ-aminobutyric acid type A (GABAA) receptor complex plays a central role in the modulation of anxiety. Conditioned fear and anxiety-like behaviors have many similarities at the neuroanatomical and pharmacological levels. The radioactive GABA/BZR receptor antagonist, fluorine-18-labeled flumazenil, [18F]flumazenil, behaves as a potential PET imaging agent for the evaluation of cortical damage of the brain in stroke, alcoholism, and for Alzheimer disease investigation. The main goal of our study was to investigate a fully automated nucleophilic fluorination system, with solid extraction purification, developed to replace traditional preparation methods, and to detect underlying expressions of contextual fear and characterize the distribution of GABAA receptors in fear-conditioned rats by [18F]flumazenil. A carrier-free nucleophilic fluorination method using an automatic synthesizer with direct labeling of a nitro-flumazenil precursor was implemented. The semi-preparative high-performance liquid chromatography (HPLC) purification method (RCY = 15–20%) was applied to obtain high purity [18F]flumazenil. Nano-positron emission tomography (NanoPET)/computed tomography (CT) imaging and ex vivo autoradiography were used to analyze the fear conditioning of rats trained with 1–10 tone-foot-shock pairings. The anxiety rats had a significantly lower cerebral accumulation (in the amygdala, prefrontal cortex, cortex, and hippocampus) of fear conditioning. Our rat autoradiography results also supported the findings of PET imaging. Key findings were obtained by developing straightforward labeling and purification procedures that can be easily adapted to commercially available modules for the high radiochemical purity of [18F]flumazenil. The use of an automatic synthesizer with semi-preparative HPLC purification would be a suitable reference method for new drug studies of GABAA/BZR receptors in the future.
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17
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Maresh K, Papageorgiou A, Ridout D, Harrison NA, Mandy W, Skuse D, Muntoni F. Startle responses in Duchenne muscular dystrophy: a novel biomarker of brain dystrophin deficiency. Brain 2023; 146:252-265. [PMID: 35136951 PMCID: PMC9825594 DOI: 10.1093/brain/awac048] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/20/2021] [Accepted: 01/16/2022] [Indexed: 01/12/2023] Open
Abstract
Duchenne muscular dystrophy (DMD) is characterized by loss of dystrophin in muscle, however patients also have variable degree of intellectual disability and neurobehavioural co-morbidities. In contrast to muscle, in which a single full-length dystrophin isoform (Dp427) is produced, multiple isoforms are produced in the brain, and their deficiency accounts for the variability of CNS manifestations, with increased risk of comorbidities in patients carrying mutations affecting the 3' end of the gene, which disrupt expression of shorter Dp140 and Dp71 isoforms. A mouse model (mdx mouse) lacks Dp427 in muscle and CNS and exhibits exaggerated startle responses to threat, linked to the deficiency of dystrophin in limbic structures such as the amygdala, which normalize with postnatal brain dystrophin-restoration therapies. A pathological startle response is not a recognized feature of DMD, and its characterization has implications for improved clinical management and translational research. To investigate startle responses in DMD, we used a novel fear-conditioning task in an observational study of 56 males aged 7-12 years (31 affected boys, mean age 9.7 ± 1.8 years; 25 controls, mean age 9.6 ± 1.4 years). Trials of two neutral visual stimuli were presented to participants: one 'safe' cue presented alone; one 'threat' cue paired with an aversive noise to enable conditioning of physiological startle responses (skin conductance response and heart rate). Retention of conditioned physiological responses was subsequently tested by presenting both cues without the aversive noise in an 'Extinction' phase. Primary outcomes were the initial unconditioned skin conductance and change in heart rate responses to the aversive 'threat' and acquisition and retention of conditioned responses after conditioning. Secondary and exploratory outcomes were neuropsychological measures and genotype associations. The mean unconditioned skin conductance response was greater in the DMD group than controls [mean difference 3.0 µS (1.0, 5.1); P = 0.004], associated with a significant threat-induced bradycardia only in the patient group [mean difference -8.7 bpm (-16.9, -0.51); P = 0.04]. Participants with DMD found the task more aversive than controls, with increased early termination rates during the Extinction phase (26% of DMD group versus 0% of controls; P = 0.007). This study provides the first evidence that boys with DMD show similar increased unconditioned startle responses to threat to the mdx mouse, which in the mouse respond to brain dystrophin restoration. Our study provides new insights into the neurobiology underlying the complex neuropsychiatric co-morbidities in DMD and defines an objective measure of this CNS phenotype, which will be valuable for future CNS-targeted dystrophin-restoration studies.
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Affiliation(s)
- Kate Maresh
- Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
- Queen Square Centre for Neuromuscular Diseases, University College London, London WC1N 3BG, UK
| | - Andriani Papageorgiou
- Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
| | - Deborah Ridout
- Population, Policy and Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
- NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
| | - Neil A Harrison
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - William Mandy
- Department of Clinical, Educational and Health Psychology, University College London, London WC1E 6BT, UK
| | - David Skuse
- Department of Behavioural and Brain Sciences, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
| | - Francesco Muntoni
- Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
- Queen Square Centre for Neuromuscular Diseases, University College London, London WC1N 3BG, UK
- NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
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18
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Ali AB, Islam A, Constanti A. The fate of interneurons, GABA A receptor sub-types and perineuronal nets in Alzheimer's disease. Brain Pathol 2022; 33:e13129. [PMID: 36409151 PMCID: PMC9836378 DOI: 10.1111/bpa.13129] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/12/2022] [Indexed: 11/23/2022] Open
Abstract
Alzheimer's disease (AD) is the most common neurological disease, which is associated with gradual memory loss and correlated with synaptic hyperactivity and abnormal oscillatory rhythmic brain activity that precedes phenotypic alterations and is partly responsible for the spread of the disease pathology. Synaptic hyperactivity is thought to be because of alteration in the homeostasis of phasic and tonic synaptic inhibition, which is orchestrated by the GABAA inhibitory system, encompassing subclasses of interneurons and GABAA receptors, which play a vital role in cognitive functions, including learning and memory. Furthermore, the extracellular matrix, the perineuronal nets (PNNs) which often go unnoticed in considerations of AD pathology, encapsulate the inhibitory cells and neurites in critical brain regions and have recently come under the light for their crucial role in synaptic stabilisation and excitatory-inhibitory balance and when disrupted, serve as a potential trigger for AD-associated synaptic imbalance. Therefore, in this review, we summarise the current understanding of the selective vulnerability of distinct interneuron subtypes, their synaptic and extrasynaptic GABAA R subtypes as well as the changes in PNNs in AD, detailing their contribution to the mechanisms of disease development. We aim to highlight how seemingly unique malfunction in each component of the interneuronal GABA inhibitory system can be tied together to result in critical circuit dysfunction, leading to the irreversible symptomatic damage observed in AD.
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19
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Youssef MMM, Hamada HT, Lai ESK, Kiyama Y, El-Tabbal M, Kiyonari H, Nakano K, Kuhn B, Yamamoto T. TOB is an effector of the hippocampus-mediated acute stress response. Transl Psychiatry 2022; 12:302. [PMID: 35906220 PMCID: PMC9338090 DOI: 10.1038/s41398-022-02078-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/14/2022] [Accepted: 07/19/2022] [Indexed: 11/25/2022] Open
Abstract
Stress affects behavior and involves critical dynamic changes at multiple levels ranging from molecular pathways to neural circuits and behavior. Abnormalities at any of these levels lead to decreased stress resilience and pathological behavior. However, temporal modulation of molecular pathways underlying stress response remains poorly understood. Transducer of ErbB2.1, known as TOB, is involved in different physiological functions, including cellular stress and immediate response to stimulation. In this study, we investigated the role of TOB in psychological stress machinery at molecular, neural circuit, and behavioral levels. Interestingly, TOB protein levels increased after mice were exposed to acute stress. At the neural circuit level, functional magnetic resonance imaging (fMRI) suggested that intra-hippocampal and hippocampal-prefrontal connectivity were dysregulated in Tob knockout (Tob-KO) mice. Electrophysiological recordings in hippocampal slices showed increased postsynaptic AMPAR-mediated neurotransmission, accompanied by decreased GABA neurotransmission and subsequently altered Excitatory/Inhibitory balance after Tob deletion. At the behavioral level, Tob-KO mice show abnormal, hippocampus-dependent, contextual fear conditioning and extinction, and depression-like behaviors. On the other hand, increased anxiety observed in Tob-KO mice is hippocampus-independent. At the molecular level, we observed changes in factors involved in stress response like decreased stress-induced LCN2 expression and ERK phosphorylation, as well as increased MKP-1 expression. This study introduces TOB as an important modulator in the hippocampal stress signaling machinery. In summary, we reveal a molecular pathway and neural circuit mechanism by which Tob deletion contributes to expression of pathological stress-related behavior.
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Affiliation(s)
- Mohieldin M M Youssef
- Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
| | - Hiro Taiyo Hamada
- Neural Computation Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
| | - Esther Suk King Lai
- Neural Circuit Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
| | - Yuji Kiyama
- Laboratory of Biochemistry and Molecular Biology, Graduate school of medical and dental sciences, Kagoshima University, Kagoshima, Japan
| | - Mohamed El-Tabbal
- Optical Neuroimaging Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
| | - Hiroshi Kiyonari
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan
| | - Kohei Nakano
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan
| | - Bernd Kuhn
- Optical Neuroimaging Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
| | - Tadashi Yamamoto
- Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
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20
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Larivee R, Johnson N, Freedgood NR, Cameron HA, Schoenfeld TJ. Inhibition of Hippocampal Neurogenesis Starting in Adolescence Increases Anxiodepressive Behaviors Amid Stress. Front Behav Neurosci 2022; 16:940125. [PMID: 35864848 PMCID: PMC9294378 DOI: 10.3389/fnbeh.2022.940125] [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: 05/10/2022] [Accepted: 06/16/2022] [Indexed: 11/16/2022] Open
Abstract
Stressors during the adolescent period can affect development of the brain and have long-lasting impacts on behavior. Specifically, adolescent stress impairs hippocampal neurogenesis and can increase risk for anxiety, depression, and a dysregulated stress response in adulthood. In order to model the functional effects of reduced hippocampal neurogenesis during adolescence, a transgenic neurogenesis ablation rat model was used to suppress neurogenesis during the adolescent period and test anxiodepressive behaviors and stress physiology during adulthood. Wildtype and transgenic (TK) rats were given valganciclovir during the first two weeks of adolescence (4-6 weeks old) to knock down neurogenesis in TK rats. Starting in young adulthood (13 weeks old), blood was sampled for corticosterone at several time points following acute restraint stress to measure negative feedback of the stress response, and rats were tested on a battery of anxiodepressive tests at baseline and following acute restraint stress. Although TK rats had large reductions in both cell proliferation during adolescence, as measured by bromodeoxyuridine (BrdU), and ongoing neurogenesis in adulthood (by doublecortin), resulting in decreased volume of the dentate gyrus, negative feedback of the stress response following acute restraint was similar across all rats. Despite similar stress responses, TK rats showed higher anxiety-like behavior at baseline. In addition, only TK rats had increased depressive-like behavior when tested after acute stress. Together, these results suggest that long-term neurogenesis ablation starting in adolescence produces hippocampal atrophy and increases behavioral caution and despair amid stressful environments.
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Affiliation(s)
- Rachelle Larivee
- Department of Psychological Science and Neuroscience, Belmont University, Nashville, TN, United States
| | - Natalie Johnson
- Department of Psychological Science and Neuroscience, Belmont University, Nashville, TN, United States
| | - Natalie R. Freedgood
- Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States
| | - Heather A. Cameron
- Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States
| | - Timothy J. Schoenfeld
- Department of Psychological Science and Neuroscience, Belmont University, Nashville, TN, United States
- *Correspondence: Timothy J. Schoenfeld,
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Castricum J, Birkenhager TK, Kushner SA, Elgersma Y, Tulen JHM. Cortical Inhibition and Plasticity in Major Depressive Disorder. Front Psychiatry 2022; 13:777422. [PMID: 35153873 PMCID: PMC8825489 DOI: 10.3389/fpsyt.2022.777422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 01/05/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Major depressive disorder (MDD) is a severe psychiatric disorder that is associated with various cognitive impairments, including learning and memory deficits. As synaptic plasticity is considered an important mechanism underlying learning and memory, deficits in cortical plasticity might play a role in the pathophysiology of patients with MDD. We used Transcranial Magnetic Stimulation (TMS) to assess inhibitory neurotransmission and cortical plasticity in the motor cortex of MDD patients and controls. METHODS We measured the cortical silent period (CSP) and short interval cortical inhibition (SICI), as well as intermittent theta-burst stimulation (iTBS), in 9 drug-free MDD inpatients and 18 controls. RESULTS The overall response to the CSP, SICI, and iTBS paradigms was not significantly different between the patient and control groups. iTBS induction resulted in significant potentiation after 20 mins in the control group (t (17) = -2.8, p = 0.01), whereas no potentiation was observed in patients. CONCLUSIONS Potentiation of MEP amplitudes was not observed within the MDD group. No evidence was found for medium-to-large effect size differences in CSP and SICI measures in severely depressed drug-free patients, suggesting that reduced cortical inhibition is unlikely to be a robust correlate of the pathophysiological mechanism in MDD. However, these findings should be interpreted with caution due to the high inter-subject variability and the small sample size. SIGNIFICANCE These findings advance our understanding of neurophysiological functioning in drug-free severely depressed inpatients.
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Affiliation(s)
- Jesminne Castricum
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands.,Department of Neuroscience, Erasmus University Medical Center, Rotterdam, Netherlands.,Department of Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands.,ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, Netherlands
| | - Tom K Birkenhager
- Department of Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Steven A Kushner
- Department of Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Ype Elgersma
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands.,Department of Neuroscience, Erasmus University Medical Center, Rotterdam, Netherlands.,ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, Netherlands
| | - Joke H M Tulen
- Department of Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands.,ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, Netherlands
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22
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Belelli D, Hales TG, Lambert JJ, Luscher B, Olsen R, Peters JA, Rudolph U, Sieghart W. GABA A receptors in GtoPdb v.2021.3. IUPHAR/BPS GUIDE TO PHARMACOLOGY CITE 2021; 2021. [PMID: 35005623 DOI: 10.2218/gtopdb/f72/2021.3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The GABAA receptor is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, 5-HT3 and strychnine-sensitive glycine receptors. GABAA receptor-mediated inhibition within the CNS occurs by fast synaptic transmission, sustained tonic inhibition and temporally intermediate events that have been termed 'GABAA, slow' [45]. GABAA receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six α, three β, three γ, one δ, three ρ, one ε, one π and one θ GABAA receptor subunits have been reported in mammals [278, 235, 236, 283]. The π-subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist (e.g. α4- and α6- (both not functional) α5-, β2-, β3- and γ2), along with RNA editing of the α3 subunit [71]. The three ρ-subunits, (ρ1-3) function as either homo- or hetero-oligomeric assemblies [359, 50]. Receptors formed from ρ-subunits, because of their distinctive pharmacology that includes insensitivity to bicuculline, benzodiazepines and barbiturates, have sometimes been termed GABAC receptors [359], but they are classified as GABA A receptors by NC-IUPHAR on the basis of structural and functional criteria [16, 235, 236]. Many GABAA receptor subtypes contain α-, β- and γ-subunits with the likely stoichiometry 2α.2β.1γ [168, 235]. It is thought that the majority of GABAA receptors harbour a single type of α- and β - subunit variant. The α1β2γ2 hetero-oligomer constitutes the largest population of GABAA receptors in the CNS, followed by the α2β3γ2 and α3β3γ2 isoforms. Receptors that incorporate the α4- α5-or α 6-subunit, or the β1-, γ1-, γ3-, δ-, ε- and θ-subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain α6- and δ-subunits in cerebellar granule cells, or an α4- and δ-subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA [209, 272, 83, 19, 288]. GABA binding occurs at the β+/α- subunit interface and the homologous γ+/α- subunits interface creates the benzodiazepine site. A second site for benzodiazepine binding has recently been postulated to occur at the α+/β- interface ([254]; reviewed by [282]). The particular α-and γ-subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either α4- or α6-subunits are not recognised by 'classical' benzodiazepines, such as flunitrazepam (but see [356]). The trafficking, cell surface expression, internalisation and function of GABAA receptors and their subunits are discussed in detail in several recent reviews [52, 140, 188, 316] but one point worthy of note is that receptors incorporating the γ2 subunit (except when associated with α5) cluster at the postsynaptic membrane (but may distribute dynamically between synaptic and extrasynaptic locations), whereas as those incorporating the δ subunit appear to be exclusively extrasynaptic. NC-IUPHAR [16, 235, 3, 2] class the GABAA receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABAA receptors are classed as conclusively identified (i.e., α1β2γ2, α1βγ2, α3βγ2, α4βγ2, α4β2δ, α4β3δ, α5βγ2, α6βγ2, α6β2δ, α6β3δ and ρ) with further receptor isoforms occurring with high probability, or only tentatively [235, 236]. It is beyond the scope of this Guide to discuss the pharmacology of individual GABAA receptor isoforms in detail; such information can be gleaned in the reviews [16, 95, 168, 173, 143, 278, 216, 235, 236] and [9, 10]. Agents that discriminate between α-subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example via β-subunit selectivity, are indicated in the text below. The distinctive agonist and antagonist pharmacology of ρ receptors is summarised in the table and additional aspects are reviewed in [359, 50, 145, 223]. Several high-resolution cryo-electron microscopy structures have been described in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam [198].
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23
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Hossain R, Al-Khafaji K, Khan RA, Sarkar C, Islam MS, Dey D, Jain D, Faria F, Akbor R, Atolani O, Oliveira SMR, Siyadatpanah A, Pereira MDL, Islam MT. Quercetin and/or Ascorbic Acid Modulatory Effect on Phenobarbital-Induced Sleeping Mice Possibly through GABA A and GABA B Receptor Interaction Pathway. Pharmaceuticals (Basel) 2021; 14:ph14080721. [PMID: 34451819 PMCID: PMC8398796 DOI: 10.3390/ph14080721] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/28/2022] Open
Abstract
Depressive disorder is a recurrent illness that affects large numbers of the general population worldwide. In recent years, the goal of depression treatment has moved from symptomatic response to that of full remission. However, treatment-resistant depression is a major challenge in the treatment of depression or depression-related disorders. Consensus opinion, therefore, suggests that effective combined aggressive initial treatment is the most appropriate strategy. This study aimed to evaluate the effects of quercetin (QUR) and/or ascorbic acid (AA) on Phenobarbital-induced sleeping mice. QUR (50 mg/kg) and/or AA (25 mg/kg) with or without intraperitoneally pre-treated with GABA receptor agonist (diazepam: 2 mg/kg, i.p.) or antagonist (Flumazenil: 2.5 mg/kg, i.p.) to underscore the effects, as well as the possible involvement of the GABA receptor in the modulatory action of QUR and AA in sleeping mice. Additionally, an in silico study was undertaken to predict the involvement of GABA receptors in the sleep mechanism. Findings suggest that the pretreatment of QUR and AA modulated the onset and duration of action of the standard drugs in experimental animals. The acute administration of QUR and/or AA significantly (p < 0.05) reversed the DZP-mediated onset of action and slightly reversed the duration of sleep time in comparison to the vehicle (control) group. A further combination of QUR or AA with the FLU resulted in an enhancement of the onset of action while reducing the duration of action, suggesting a FLU-like effect on the test animals. In in silico studies, AA and QUR showed good to moderate binding affinities with GABAA and GABAB receptors. Both QUR and AA produced a stimulatory-like effect on mice, possibly through the GABAA and GABAB receptor interaction pathways. Further studies are necessary to verify this activity and clarify the exact mechanism of action(s) involved.
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Affiliation(s)
- Rajib Hossain
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
| | - Khattab Al-Khafaji
- Department of Chemistry, Faculty of Arts and Sciences, Gaziantep University, 27310 Gaziantep, Turkey;
| | - Rasel Ahmed Khan
- Pharmacy Discipline, Life Science School, Khulna University, Khulna 9280, Bangladesh;
| | - Chandan Sarkar
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
| | - Md. Shahazul Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
| | - Dipta Dey
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj 8100, Bangladesh;
| | - Divya Jain
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Vanasthali 304022, Rajasthan, India;
| | - Farhana Faria
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
| | - Rukaya Akbor
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
| | - Olubunmi Atolani
- Department of Chemistry, University of Ilorin, Ilorin P.M.B. 1515, Nigeria;
| | - Sónia M. R. Oliveira
- CICECO-Aveiro Institute of Materials & Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal;
- Hunter Medical Research Institute, New Lambton, NSW 2305, Australia
| | - Abolghasem Siyadatpanah
- Ferdows School of Paramedical and Health, Birjand University of Medical Sciences, Birjand 9717853577, Iran;
| | - Maria de Lourdes Pereira
- CICECO-Aveiro Institute of Materials & Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal;
- Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
- Correspondence: (M.d.L.P.); (M.T.I.)
| | - Muhammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
- Correspondence: (M.d.L.P.); (M.T.I.)
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24
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Fogaça MV, Wu M, Li C, Li XY, Picciotto MR, Duman RS. Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses. Mol Psychiatry 2021; 26:3277-3291. [PMID: 33070149 PMCID: PMC8052382 DOI: 10.1038/s41380-020-00916-y] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 09/15/2020] [Accepted: 10/05/2020] [Indexed: 12/16/2022]
Abstract
Major depressive disorder (MDD) is associated with alterations of GABAergic interneurons, notably somatostatin (Sst) as well as parvalbumin (Pvalb), in cortical brain areas. In addition, the antidepressant effects of rapid-acting drugs are thought to occur via inhibition of GABA interneurons. However, the impact of these interneuron subtypes in affective behaviors as well as in the effects of rapid-acting antidepressants remains to be determined. Here, we used a Cre-dependent DREADD-chemogenetic approach to determine if inhibition of GABA interneurons in the mPFC of male mice is sufficient to produce antidepressant actions, and conversely if activation of these interneurons blocks the rapid and sustained antidepressant effects of scopolamine, a nonselective acetylcholine muscarinic receptor antagonist. Chemogenetic inhibition of all GABA interneurons (Gad1+), as well as Sst+ and Pvalb+ subtypes in the mPFC produced dose and time-dependent antidepressant effects in the forced swim and novelty suppressed feeding tests, and increased synaptic plasticity. In contrast, stimulation of Gad1, Sst, or Pvalb interneurons in mPFC abolished the effects of scopolamine and prevented scopolamine induction of synaptic plasticity. The results demonstrate that transient inhibition of GABA interneurons promotes synaptic plasticity that underlies rapid antidepressant responses.
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Affiliation(s)
- Manoela V. Fogaça
- Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06519, USA,Corresponding author: Manoela V. Fogaça, 34 Park Street, New Haven, Connecticut 06519 USA, ; , Phone: +1 (203) 974-7726
| | - Min Wu
- Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06519, USA
| | - Chan Li
- Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06519, USA
| | - Xiao-Yuan Li
- Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06519, USA
| | - Marina R. Picciotto
- Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06519, USA
| | - Ronald S. Duman
- Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06519, USA
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25
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Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice. Cell Death Dis 2021; 12:553. [PMID: 34050134 PMCID: PMC8163876 DOI: 10.1038/s41419-021-03846-x] [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: 02/12/2021] [Accepted: 05/17/2021] [Indexed: 02/04/2023]
Abstract
Mutations in the GABRG2 gene encoding the γ-aminobutyric acid (GABA) A receptor gamma 2 subunit are associated with genetic epilepsy with febrile seizures plus, febrile seizures plus, febrile seizures, and other symptoms of epilepsy. However, the mechanisms underlying Gabrg2-mediated febrile seizures are poorly understood. Here, we used the Cre/loxP system to generate conditional knockout (CKO) mice with deficient Gabrg2 in the hippocampus and neocortex. Heterozygous CKO mice (Gabrg2fl/wtCre+) exhibited temperature-dependent myoclonic jerks, generalised tonic-clonic seizures, increased anxiety-like symptoms, and a predisposition to induce seizures. Cortical electroencephalography showed the hyperexcitability in response to temperature elevation in Gabrg2fl/wtCre+ mice, but not in wild-type mice. Gabrg2fl/wtCre+ mice exhibited spontaneous seizures and susceptibility to temperature-induced seizures. Loss of neurons were observed in cortical layers V-VI and hippocampus of Gabrg2fl/wtCre+ mice. Furthermore, the latency of temperature- or pentylenetetrazol-induced seizures were significantly decreased in Gabrg2fl/wtCre+ mice compared with wild-type mice. In summary, Gabrg2fl/wtCre+ mice with Gabrg2 deletion in the neocortex and hippocampus reproduce many features of febrile seizures and therefore provide a novel model to further understand this syndrome at the cellular and molecular level.
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26
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Altered interhemispheric signal propagation in schizophrenia and depression. Clin Neurophysiol 2021; 132:1604-1611. [PMID: 34030057 DOI: 10.1016/j.clinph.2021.03.039] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 02/04/2021] [Accepted: 03/19/2021] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Altered interhemispheric connectivity is implicated in the pathophysiology of schizophrenia (SCZ) and major depressive disorder (MDD) and may account for deficits in lateralized cognitive processes. We measured transcranial magnetic stimulation evoked interhemispheric signal propagation (ISP), a non-invasive measure of transcallosal connectivity, and hypothesized that the SCZ and MDD groups will have increased ISP compared to healthy controls. METHODS We evaluated ISP over the dorsolateral prefrontal cortex in 34 patients with SCZ and 34 patients with MDD compared to 32 age and sex-matched healthy controls. RESULTS ISP was significantly increased in patients with SCZ and patients with MDD compared to healthy controls but did not differ between patient groups. There were no effects of antidepressant, antipsychotic, and benzodiazepine medications on ISP and our results remained unchanged after re-analysis with a region of interest method. CONCLUSION Altered ISP was found in both SCZ and MDD patient groups. This indicates that disruptions of interhemispheric signaling processes can be indexed with ISP across psychiatric populations. SIGNIFICANCE These findings enhance our knowledge of the physiological mechanisms of interhemispheric imbalances in SCZ and MDD, which may serve as potential treatment targets in future patients.
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27
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Obaidullah AJ, Alanazi MM, Alsaif NA, Mahdi WA, Fantoukh OI, Tareq AM, Sami SA, Alqahtani AM, Emran TB. Deeper Insights on Cnesmone javanica Blume Leaves Extract: Chemical Profiles, Biological Attributes, Network Pharmacology and Molecular Docking. PLANTS (BASEL, SWITZERLAND) 2021; 10:728. [PMID: 33917986 PMCID: PMC8068331 DOI: 10.3390/plants10040728] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/05/2021] [Accepted: 04/06/2021] [Indexed: 01/14/2023]
Abstract
This study assessed the anxiolytic and antidepressant activities of a methanol leaves extract of Cnesmone javanica (CV) in Swiss albino mice. The study found a significant increase in the percentage of time spent in the open arms of an elevated plus maze and in the incidence of head dipping in hole-board tests following the administration of 400 mg/kg of CV or 1 mg/kg diazepam. Moreover, a significant (p < 0.001) dose-dependent reduction was observed in the immobility time following CV (200 and 400 mg/kg) and fluoxetine (20 mg/kg) administration for forced swimming and tail suspension tests. Gas chromatography-mass spectroscopy (GC-MS) analysis identified 62 compounds in CV, consisting primarily of phenols, terpenoids, esters, and other organic compounds. A molecular docking study was performed to assess the anxiolytic and antidepressant effects of 45 selected compounds against human serotonin transporter and potassium channels receptors. Network pharmacology was performed to predict the pathways involved in these neuropharmacological effects. Overall, CV demonstrated significant and dose-dependent anxiolytic and antidepressant effects due to the presence of several bioactive phytoconstituents, which should be further explored using more advanced and in-depth mechanistic research.
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Affiliation(s)
- Ahmad J. Obaidullah
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (M.M.A.); (N.A.A.)
| | - Mohammed M. Alanazi
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (M.M.A.); (N.A.A.)
| | - Nawaf A. Alsaif
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (M.M.A.); (N.A.A.)
| | - Wael A. Mahdi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;
| | - Omer I. Fantoukh
- Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;
| | - Abu Montakim Tareq
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh;
| | - Saad Ahmed Sami
- Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh;
| | - Ali M. Alqahtani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia;
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
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28
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Qu S, Zhou C, Howe R, Shen W, Huang X, Catron M, Hu N, Macdonald RL. The K328M substitution in the human GABA A receptor gamma2 subunit causes GEFS+ and premature sudden death in knock-in mice. Neurobiol Dis 2021; 152:105296. [PMID: 33582225 PMCID: PMC8243844 DOI: 10.1016/j.nbd.2021.105296] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/19/2021] [Accepted: 02/08/2021] [Indexed: 01/03/2023] Open
Affiliation(s)
- Shimian Qu
- Departments of Neurology, Vanderbilt University, Nashville, TN 37232, United States of America.
| | - Chengwen Zhou
- Departments of Neurology, Vanderbilt University, Nashville, TN 37232, United States of America.
| | - Rachel Howe
- Departments of Neurology, Vanderbilt University, Nashville, TN 37232, United States of America.
| | - Wangzhen Shen
- Departments of Neurology, Vanderbilt University, Nashville, TN 37232, United States of America.
| | - Xuan Huang
- Departments of Neurology, Vanderbilt University, Nashville, TN 37232, United States of America.
| | - Mackenzie Catron
- Departments of Neurology, Vanderbilt University, Nashville, TN 37232, United States of America.
| | - Ningning Hu
- Departments of Neurology, Vanderbilt University, Nashville, TN 37232, United States of America.
| | - Robert L Macdonald
- Departments of Neurology, Vanderbilt University, Nashville, TN 37232, United States of America; Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, United States of America; Pharmacology, Vanderbilt University, Nashville, TN 37232, United States of America.
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29
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Vanaveski T, Molchanova S, Pham DD, Schäfer A, Pajanoja C, Narvik J, Srinivasan V, Urb M, Koivisto M, Vasar E, Timmusk T, Minkeviciene R, Eriksson O, Lalowski M, Taira T, Korhonen L, Voikar V, Lindholm D. PGC-1α Signaling Increases GABA(A) Receptor Subunit α2 Expression, GABAergic Neurotransmission and Anxiety-Like Behavior in Mice. Front Mol Neurosci 2021; 14:588230. [PMID: 33597848 PMCID: PMC7882546 DOI: 10.3389/fnmol.2021.588230] [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: 07/28/2020] [Accepted: 01/14/2021] [Indexed: 12/23/2022] Open
Abstract
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondria biogenesis and cell stress playing a role in metabolic and degenerative diseases. In the brain PGC-1α expression has been localized mainly to GABAergic interneurons but its overall role is not fully understood. We observed here that the protein levels of γ-aminobutyric acid (GABA) type A receptor-α2 subunit (GABARα2) were increased in hippocampus and brain cortex in transgenic (Tg) mice overexpressing PGC-1α in neurons. Along with this, GABARα2 expression was enhanced in the hippocampus of the PGC-1α Tg mice, as shown by quantitative PCR. Double immunostaining revealed that GABARα2 co-localized with the synaptic protein gephyrin in higher amounts in the striatum radiatum layer of the hippocampal CA1 region in the Tg compared with Wt mice. Electrophysiology revealed that the frequency of spontaneous and miniature inhibitory postsynaptic currents (mIPSCs) was increased in the CA1 region in the Tg mice, indicative of an augmented GABAergic transmission. Behavioral tests revealed an increase for anxiety-like behavior in the PGC-1α Tg mice compared with controls. To study whether drugs acting on PPARγ can affect GABARα2, we employed pioglitazone that elevated GABARα2 expression in primary cultured neurons. Similar results were obtained using the specific PPARγ agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino) ethyl]-L-tyrosine hydrate (GW1929). These results demonstrate that PGC-1α regulates GABARα2 subunits and GABAergic neurotransmission in the hippocampus with behavioral consequences. This indicates further that drugs like pioglitazone, widely used in the treatment of type 2 diabetes, can influence GABARα2 expression via the PPARγ/PGC-1α system.
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Affiliation(s)
- Taavi Vanaveski
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland.,Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.,Quretec Ltd., Tartu, Estonia
| | - Svetlana Molchanova
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Dan Duc Pham
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Annika Schäfer
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Ceren Pajanoja
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Jane Narvik
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.,Quretec Ltd., Tartu, Estonia
| | - Vignesh Srinivasan
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | | | - Maria Koivisto
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Eero Vasar
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Tönis Timmusk
- Protobios LCC, Tallinn, Estonia.,Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | | | - Ove Eriksson
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland
| | - Maciej Lalowski
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.,Meilahti Clinical Proteomics Core Facility, HiLIFE, University of Helsinki, Helsinki, Finland.,Department of Biomedical Proteomics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland
| | - Tomi Taira
- Department of Veterinary Biosciences, Faculty of Veterinary Medicine and Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Laura Korhonen
- Department of Child and Adolescent Psychiatry and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Vootele Voikar
- Neuroscience Center and Laboratory Animal Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Dan Lindholm
- Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
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Schäfer J, Förster L, Mey I, Papadopoulos T, Brose N, Steinem C. Neuroligin-2 dependent conformational activation of collybistin reconstituted in supported hybrid membranes. J Biol Chem 2020; 295:18604-18613. [PMID: 33127642 PMCID: PMC7939476 DOI: 10.1074/jbc.ra120.015347] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/27/2020] [Indexed: 12/23/2022] Open
Abstract
The assembly of the postsynaptic transmitter sensing machinery at inhibitory nerve cell synapses requires the intimate interplay between cell adhesion proteins, scaffold and adaptor proteins, and γ-aminobutyric acid (GABA) or glycine receptors. We developed an in vitro membrane system to reconstitute this process, to identify the essential protein components, and to define their mechanism of action, with a specific focus on the mechanism by which the cytosolic C terminus of the synaptic cell adhesion protein Neuroligin-2 alters the conformation of the adaptor protein Collybistin-2 and thereby controls Collybistin-2-interactions with phosphoinositides (PtdInsPs) in the plasma membrane. Supported hybrid membranes doped with different PtdInsPs and 1,2-dioleoyl-sn-glycero-3-{[N-(5-amino-1-carboxypentyl)iminodiacetic acid]succinyl} nickel salt (DGS-NTA(Ni)) to allow for the specific adsorption of the His6-tagged intracellular domain of Neuroligin-2 (His-cytNL2) were prepared on hydrophobically functionalized silicon dioxide substrates via vesicle spreading. Two different collybistin variants, the WT protein (CB2SH3) and a mutant that adopts an intrinsically 'open' and activated conformation (CB2SH3/W24A-E262A), were bound to supported membranes in the absence or presence of His-cytNL2. The corresponding binding data, obtained by reflectometric interference spectroscopy, show that the interaction of the C terminus of Neuroligin-2 with Collybistin-2 induces a conformational change in Collybistin-2 that promotes its interaction with distinct membrane PtdInsPs.
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Affiliation(s)
- Jonas Schäfer
- Institute for Organic and Biomolecular Chemistry, Georg August University, Göttingen, Germany
| | - Lucas Förster
- Institute for Organic and Biomolecular Chemistry, Georg August University, Göttingen, Germany
| | - Ingo Mey
- Institute for Organic and Biomolecular Chemistry, Georg August University, Göttingen, Germany
| | | | - Nils Brose
- Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
| | - Claudia Steinem
- Institute for Organic and Biomolecular Chemistry, Georg August University, Göttingen, Germany; Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany.
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31
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Jefferson SJ, Feng M, Chon UR, Guo Y, Kim Y, Luscher B. Disinhibition of somatostatin interneurons confers resilience to stress in male but not female mice. Neurobiol Stress 2020; 13:100238. [PMID: 33344694 PMCID: PMC7739040 DOI: 10.1016/j.ynstr.2020.100238] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/22/2020] [Accepted: 07/01/2020] [Indexed: 12/16/2022] Open
Abstract
Chronic stress represents a vulnerability factor for anxiety and depressive disorders and has been widely used to model aspects of these disorders in rodents. Disinhibition of somatostatin (SST)-positive GABAergic interneurons in mice by deletion of γ2 GABAA receptors selectively from these cells (SSTCre:γ2f/f mice) has been shown to result in behavioral and biochemical changes that mimic the responses to antidepressant doses of ketamine. Here we explored the extent to which SSTCre:γ2f/f mice exhibit resilience to unpredictable chronic mild stress (UCMS). We found that male SSTCre:γ2f/f mice are resilient to UCMS-induced (i) reductions in weight gain, (ii) reductions in SST-immuno-positive cells in medial prefrontal cortex (mPFC), (iii) increases in phosphorylation of eukaryotic elongation factor 2 (eEF2) in mPFC, and (iv) increased anxiety in a novelty suppressed feeding test. Female SSTCre:γ2f/f mice were resilient to UCMS-induced reductions in SST-immuno-positive cells indistinguishably from males. However, in contrast to males, they showed no UCMS effects on weight gain independent of genotype. Moreover, in mPFC of female γ2f/f control mice, UCMS resulted in paradoxically reduced p-EF2 levels without stress effects in the SSTCre:γ2f/f mutants. Lastly, female SSTCre:γ2f/f mice showed increased rather than reduced UCMS induced anxiety compared to γ2f/f controls. Thus, disinhibition of SST interneurons results in behavioral resilience to UCMS selectively in male mice, along with cellular resilience of SST neurons to UCMS independent of sex. Thus, mechanisms underlying vulnerability and resilience to stress are sex specific and map to mPFC rather than hippocampus but appear unrelated to changes in expression of SST as a marker of corresponding interneurons.
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Affiliation(s)
- Sarah J. Jefferson
- Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA
- Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA
| | - Mengyang Feng
- Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA
- Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA
| | - URee Chon
- Department of Neural and Behavioral Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, 17033, USA
| | - Yao Guo
- Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA
- Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA
| | - Yongsoo Kim
- Department of Neural and Behavioral Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, 17033, USA
| | - Bernhard Luscher
- Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA
- Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PA, 16802, USA
- Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA
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Sbrini G, Brivio P, Bosch K, Homberg JR, Calabrese F. Enrichment Environment Positively Influences Depression- and Anxiety-Like Behavior in Serotonin Transporter Knockout Rats through the Modulation of Neuroplasticity, Spine, and GABAergic Markers. Genes (Basel) 2020; 11:genes11111248. [PMID: 33114023 PMCID: PMC7690660 DOI: 10.3390/genes11111248] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 02/06/2023] Open
Abstract
The serotonin transporter (5-HTT in humans, SERT in rodents) is the main regulator of serotonergic transmission in the brain. The short allelic variant of the 5-HTT gene is in humans associated with psychopathologies and may enhance the vulnerability to develop depression after exposure to stressful events. Interestingly, the short allele also increases the sensitivity to a positive environment, which may buffer the vulnerability to depression. Since this polymorphism does not exist in rodents, male SERT knockout (SERT−/−) rats were tested to explore the molecular mechanisms based on this increased predisposition. This article investigates the influences of a positive manipulation, namely, enriched environment (EE), on the depressive-like behavior observed in SERT−/− rats. We found that one month of EE exposure normalized the anhedonic and anxious-like phenotype characteristics of this animal model. Moreover, we observed that EE exposure also restored the molecular alterations in the prefrontal cortex by positively modulating the expression of the neurotrophin Bdnf, and of spines and gamma-aminobutyric acid (GABA)ergic markers. Overall, our data confirm the depression-like phenotype of SERT−/− rats and highlight the ability of EE to restore behavioral and molecular alterations, thus promoting the opportunity to use EE as a supporting non-pharmacological approach to treat mood disorders.
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Affiliation(s)
- Giulia Sbrini
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, 20133 Milan, Italy; (G.S.); (P.B.)
| | - Paola Brivio
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, 20133 Milan, Italy; (G.S.); (P.B.)
| | - Kari Bosch
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; (K.B.); (J.R.H.)
| | - Judith Regina Homberg
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; (K.B.); (J.R.H.)
| | - Francesca Calabrese
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, 20133 Milan, Italy; (G.S.); (P.B.)
- Correspondence: ; Tel.: +02-50318277
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33
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Characterization of Gut Microbiota in Prenatal Cold Stress Offspring Rats by 16S rRNA Sequencing. Animals (Basel) 2020; 10:ani10091619. [PMID: 32927774 PMCID: PMC7552136 DOI: 10.3390/ani10091619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Prenatal stress, including prenatal cold stress has long-term effects on offspring’s physical and mental health. Our previous study showed a reduction of anxiety-like behavior in offspring rats suffered from prenatal cold stress. It is well-known that gut microbiota was involved in a variety of physiological activities, such as emotion, cognition, and behavior. However, information on the comparison between prenatal cold stress and gut microbiota in offspring is limited. The current study compared the gut microbiota composition of the prenatal cold stress and non-stress offspring rats. Cold stressed during gestation period showed to change the offspring gut microbiota composition, and Bacteroides and Lactobacillus were significantly increased in prenatal cold stress offspring rat guts. With the hope, cold stress-induced negative effects of animals can be prevented by microbiological interventions. Abstract Our previous study showed a reduction of anxiety-like behavior in offspring rats suffered from prenatal cold stress; whether this was related to changes in the offspring gut microbiota is unclear. To obtain the evidence for the role of the gut microbiota in prenatal cold stress offspring, 16S rRNA sequencing technology was used. Male and female offspring rat feces were collected from a room temperature group and a prenatal cold stress group (n ≥ 8) for microbial DNA extraction, followed by 16S rRNA sequencing. The results indicated that prenatal cold stress could change the offspring’s gut microbiota composition. Prenatal cold stress significantly upregulates Lactobacillus, Lactobacillus_gasseri, Bacteroides, and Bacteroides-acidifaciens in female offspring, whereas prenatal cold stress significantly reduced Lachnospiraceae and Prevotellaceae in male offspring. These data showed the characterization of gut microbiota in prenatal cold stress offspring rats, and these data suggest that microbiological intervention in the future can potentially prevent the negative effects caused by cold stress to animals.
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Ito N, Sasaki K, Takemoto H, Kobayashi Y, Isoda H, Odaguchi H. Emotional Impairments and Neuroinflammation are Induced in Male Mice Invulnerable to Repeated Social Defeat Stress. Neuroscience 2020; 443:148-163. [PMID: 32707290 DOI: 10.1016/j.neuroscience.2020.07.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 07/10/2020] [Accepted: 07/14/2020] [Indexed: 11/26/2022]
Abstract
Prolonged stress triggers neuroinflammation, which plays a significant role in the development of depression; however, stressed people do not always suffer from depression because of individual differences in stress vulnerability. Negative cognitive bias (NCB) toward pessimistic judgment often underlies depressive episodes. However, a relationship between stress vulnerability, neuroinflammation, and NCB remains elusive. In addition, an animal model with all the traits would be a powerful tool for studying the etiology of depression and its therapeutic approaches. Accordingly, this study evaluated the effect of stress vulnerability on neuroinflammation and depression-related behaviors, including NCB in males, using a modified version of repeated social defeat stress (mRSDS) paradigm, a validated animal model of psychosocial stress. Exposure to mRSDS, consisting of 5 min of social defeat by unfamiliar CD-1 aggressor mice for five consecutive days, caused NCB, which co-occurred with depressive- and anxiety-like behaviors, and neuroinflammation in male BALB/c mice. Treatment with minocycline, an antibiotic with anti-inflammatory property, blocked mRSDS-induced depressive-like behaviors and neuroinflammation, but not NCB, indicating the limited effect of an anti-inflammatory intervention. In addition, marked differences were found in neuroinflammatory profiles and hippocampal gene expression patterns between resilient and unstressed mice, as well as between susceptible and resilient mice. Therefore, mice resilient to mRSDS are indeed not intact. Our findings provide insights into the unique features of the mRSDS model in male BALB/c mice, which could be used to investigate the etiological mechanisms underlying depression as well as bridge the gap in the relationship between stress vulnerability, neuroinflammation, and NCB in males.
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Affiliation(s)
- Naoki Ito
- Department of Clinical Research, Oriental Medicine Research Center, Kitasato University, Minato-ku, Tokyo 108-8642, Japan.
| | - Kazunori Sasaki
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba-shi, Ibaraki 305-8572, Japan; Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba-shi, Ibaraki 305-8565, Japan; Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki 305-8571, Japan
| | - Hiroaki Takemoto
- School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8642, Japan
| | - Yoshinori Kobayashi
- Department of Clinical Research, Oriental Medicine Research Center, Kitasato University, Minato-ku, Tokyo 108-8642, Japan; School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8642, Japan
| | - Hiroko Isoda
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba-shi, Ibaraki 305-8572, Japan; Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba-shi, Ibaraki 305-8565, Japan; Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki 305-8572, Japan
| | - Hiroshi Odaguchi
- Department of Clinical Research, Oriental Medicine Research Center, Kitasato University, Minato-ku, Tokyo 108-8642, Japan
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Luo ZY, Huang L, Lin S, Yin YN, Jie W, Hu NY, Hu YY, Guan YF, Liu JH, You QL, Chen YH, Luo ZC, Zhang SR, Li XW, Yang JM, Tao YM, Mei L, Gao TM. Erbin in Amygdala Parvalbumin-Positive Neurons Modulates Anxiety-like Behaviors. Biol Psychiatry 2020; 87:926-936. [PMID: 31889536 DOI: 10.1016/j.biopsych.2019.10.021] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 10/02/2019] [Accepted: 10/21/2019] [Indexed: 11/30/2022]
Abstract
BACKGROUND Anxiety disorders are the most common psychiatric diseases, affecting 28% of people worldwide within their lifetime. The excitation-inhibition imbalance in the amygdala is thought to be an underlying pathological mechanism; however, the cellular and molecular control of amygdala excitation-inhibition balance is largely unknown. METHODS By using mice expressing chemogenetic activator or inhibitor channel in amygdala parvalbumin (PV) neurons, Erbin mutant mice, and mice with Erbin specifically knocked down in amygdala PV neurons, we systematically investigated the role of amygdala PV neurons and Erbin expressed therein in the pathogenesis of anxiety disorders using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS In naïve mice, chemogenetic inhibition of PV neurons produced anxiogenic effects, suggesting an essential role in the regulation of anxiety. In stressed mice with anxiety, excitatory postsynaptic responses on amygdala PV neurons were selectively diminished, accompanied by a decreased expression of Erbin specifically in amygdala PV neurons. Remarkably, both Erbin mutant mice and amygdala PV-specific Erbin knockdown mice exhibited impaired excitatory postsynaptic responses on amygdala PV neurons and increased anxiety-like behaviors. Furthermore, chemogenetic activation of amygdala PV neurons normalized anxiety behaviors in amygdala PV-specific Erbin knockdown mice and stressed mice. CONCLUSIONS Together, these results demonstrate that Erbin in PV neurons is critical for maintaining the excitation-inhibition balance in the amygdala and reveal a novel pathophysiological mechanism for anxiety disorders.
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Affiliation(s)
- Zheng-Yi Luo
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Lang Huang
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Song Lin
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ya-Nan Yin
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Wei Jie
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Neng-Yuan Hu
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yu-Ying Hu
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yan-Fei Guan
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ji-Hong Liu
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Qiang-Long You
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yi-Hua Chen
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhou-Cai Luo
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Sheng-Rong Zhang
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiao-Wen Li
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jian-Ming Yang
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yan-Mei Tao
- Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China
| | - Lin Mei
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Tian-Ming Gao
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
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Tonon MC, Vaudry H, Chuquet J, Guillebaud F, Fan J, Masmoudi-Kouki O, Vaudry D, Lanfray D, Morin F, Prevot V, Papadopoulos V, Troadec JD, Leprince J. Endozepines and their receptors: Structure, functions and pathophysiological significance. Pharmacol Ther 2020; 208:107386. [DOI: 10.1016/j.pharmthera.2019.06.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 06/20/2019] [Indexed: 02/06/2023]
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37
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Spectroscopic investigation on alteration of dynamic properties of lipid membrane in presence of Gamma-Aminobutyric Acid (GABA). J Mol Liq 2020. [DOI: 10.1016/j.molliq.2019.111877] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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38
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Blockade of the dopaminergic neurotransmission with AMPT and reserpine induces a differential expression of genes of the dopaminergic phenotype in substantia nigra. Neuropharmacology 2019; 166:107920. [PMID: 31870855 DOI: 10.1016/j.neuropharm.2019.107920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 11/28/2019] [Accepted: 12/20/2019] [Indexed: 11/23/2022]
Abstract
Dopaminergic neurons have the ability to release Dopamine from their axons as well as from their soma and dendrites. This somatodendritically-released Dopamine induces an autoinhibition of Dopaminergic neurons mediated by D2 autoreceptors, and the stimulation of neighbor GABAergic neurons mediated by D1 receptors (D1r). Here, our results suggest that the somatodendritic release of Dopamine in the substantia nigra (SN) may stimulate GABAergic neurons that project their axons into the hippocampus. Using semiquantitative multiplex RT-PCR we show that chronic blockade of the Dopaminergic neurotransmission with both AMPT and reserpine specifically decreases the expression levels of D1r, remarkably this may be the result of an antagonistic effect between AMPT and reserpine, as they induced the expression of a different set of genes when treated by separate. Furthermore, using anterograde and retrograde tracing techniques, we found that the GABAergic neurons that express D1r also project their axons in to the CA1 region of the hippocampus. Finally, we also found that the same treatment that decreases the expression levels of D1r in SN, also induces an impairment in the performance in an appetitive learning task that requires the coding of reward as well as navigational skills. Overall, our findings show the presence of a GABAergic interconnection between the SNr and the hippocampus mediated by D1r.
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39
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Deng WK, Wang X, Zhou HC, Luo F. L-type Ca 2+ channels and charybdotoxin-sensitive Ca 2+-activated K + channels are required for reduction of GABAergic activity induced by β2-adrenoceptor in the prefrontal cortex. Mol Cell Neurosci 2019; 101:103410. [PMID: 31644953 DOI: 10.1016/j.mcn.2019.103410] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 08/26/2019] [Accepted: 09/09/2019] [Indexed: 11/18/2022] Open
Abstract
Whereas β2-adrenoceptor (β2-AR) has been reported to reduce GABAergic activity in the prefrontal cortex (PFC), the underlying cellular and molecular mechanisms have not been completely determined. Here, we showed that β2-AR agonist Clenbuterol (Clen) decreased GABAergic transmission onto PFC layer V/VI pyramidal neurons via a presynaptic mechanism without altering postsynaptic GABA receptors. Clen decreased the action potential firing rate but increased the burst afterhyperpolarization (AHP) amplitude in PFC interneurons. Application of L-type Ca2+ channel or charybdotoxin-sensitive Ca2+-activated K+ channel inhibitors blocked Clen-induced decreases in action potential firing rate, spontaneous inhibitory postsynaptic current (sIPSC) frequency and Clen-induced enhancement of AHP amplitude, suggesting that the effects of Clen involves L-type Ca2+ Channels and charybdotoxin-sensitive Ca2+-activated K+ channels. Our results provide a potential cellular mechanism by which Clen controls GABAergic neuronal activity in PFC.
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Affiliation(s)
- Wei-Ke Deng
- School of Life Sciences, Nanchang University, Nanchang 330031, China; Center for Neuropsychiatric Diseases, Institute of Life Science, Nanchang University, Nanchang 330031, China
| | - Xing Wang
- Center for Neuropsychiatric Diseases, Institute of Life Science, Nanchang University, Nanchang 330031, China
| | - Hou-Cheng Zhou
- Institute of Neurobiology & State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai 200000, China
| | - Fei Luo
- School of Life Sciences, Nanchang University, Nanchang 330031, China; Center for Neuropsychiatric Diseases, Institute of Life Science, Nanchang University, Nanchang 330031, China.
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40
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Gene knockout animal models of depression, anxiety and obsessive compulsive disorders. Psychiatr Genet 2019; 29:191-199. [DOI: 10.1097/ypg.0000000000000238] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Shi YW, Zhang Q, Cai K, Poliquin S, Shen W, Winters N, Yi YH, Wang J, Hu N, Macdonald RL, Liao WP, Kang JQ. Synaptic clustering differences due to different GABRB3 mutations cause variable epilepsy syndromes. Brain 2019; 142:3028-3044. [PMID: 31435640 PMCID: PMC6776116 DOI: 10.1093/brain/awz250] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 06/19/2019] [Accepted: 06/25/2019] [Indexed: 11/13/2022] Open
Abstract
GABRB3 is highly expressed early in the developing brain, and its encoded β3 subunit is critical for GABAA receptor assembly and trafficking as well as stem cell differentiation in embryonic brain. To date, over 400 mutations or variants have been identified in GABRB3. Mutations in GABRB3 have been increasingly recognized as a major cause for severe paediatric epilepsy syndromes such as Lennox-Gastaut syndrome, Dravet syndrome and infantile spasms with intellectual disability as well as relatively mild epilepsy syndromes such as childhood absence epilepsy. There is no plausible molecular pathology for disease phenotypic heterogeneity. Here we used a very high-throughput flow cytometry assay to evaluate the impact of multiple human mutations in GABRB3 on receptor trafficking. In this study we found that surface expression of mutant β3 subunits is variable. However, it was consistent that surface expression of partnering γ2 subunits was lower when co-expressed with mutant than with wild-type subunits. Because γ2 subunits are critical for synaptic GABAA receptor clustering, this provides an important clue for understanding the pathophysiology of GABRB3 mutations. To validate our findings further, we obtained an in-depth comparison of two novel mutations [GABRB3 (N328D) and GABRB3 (E357K)] associated with epilepsy with different severities of epilepsy phenotype. GABRB3 (N328D) is associated with the relatively severe Lennox-Gastaut syndrome, and GABRB3 (E357K) is associated with the relatively mild juvenile absence epilepsy syndrome. With functional characterizations in both heterologous cells and rodent cortical neurons by patch-clamp recordings, confocal microscopy and immunoblotting, we found that both the GABRB3 (N328D) and GABRB3 (E357K) mutations reduced total subunit expression in neurons but not in HEK293T cells. Both mutant subunits, however, were reduced on the cell surface and in synapses, but the Lennox-Gastaut syndrome mutant β3 (N328D) subunit was more reduced than the juvenile absence epilepsy mutant β3 (E357K) subunit. Interestingly, both mutant β3 subunits impaired postsynaptic clustering of wild-type GABAA receptor γ2 subunits and prevented γ2 subunits from incorporating into GABAA receptors at synapses, although by different cellular mechanisms. Importantly, wild-type γ2 subunits were reduced and less clustered at inhibitory synapses in Gabrb3+/- knockout mice. This suggests that impaired receptor localization to synapses is a common pathophysiological mechanism for GABRB3 mutations, although the extent of impairment may be different among mutant subunits. The study thus identifies the novel mechanism of impaired targeting of receptors containing mutant β3 subunits and provides critical insights into understanding how GABRB3 mutations produce severe epilepsy syndromes and epilepsy phenotypic heterogeneity.
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Affiliation(s)
- Yi-Wu Shi
- Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
| | - Qi Zhang
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
- Key laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Department of Neurology, Nantong University, 19 Qixiu Road, Nantong, JS, China
| | - Kefu Cai
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Neurology, Nantong University, 19 QiXiu Road, Nantong, JS, China
| | - Sarah Poliquin
- Neuroscience Graduate Program, Vanderbilt Brain Institute, Nashville, TN, USA
| | - Wangzhen Shen
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nathan Winters
- Neuroscience Graduate Program, Vanderbilt Brain Institute, Nashville, TN, USA
| | - Yong-Hong Yi
- Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
| | - Jie Wang
- Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
| | - Ningning Hu
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Robert L Macdonald
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Wei-Ping Liao
- Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
| | - Jing-Qiong Kang
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
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42
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Gender-dependent regulation of anxiety-like behavior by δ subunit-containing GABAA receptor during postnatal development. Neuroreport 2019; 30:753-759. [PMID: 31261237 DOI: 10.1097/wnr.0000000000001192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The δ subunit-containing GABAA receptor [GABAA(δ)R], which is exclusively situated in the extrasynaptic space, has considerable influence on emotion and behavior. Although the expression of this receptor experiences dramatic fluctuation during postnatal development, it remains unknown whether it regulates emotion in a development-dependent manner. Here, by using mice with genetic deletion of GABAA(δ)R (knockout) and their wild-type littermates, we examined the role of GABAA(δ)R in regulating anxiety-like behavior, as measured with open field test (OFT) and elevated plus maze during the transition from puberty to adulthood. We observed that for female mice, the knockout ones at puberty but not adulthood showed increased anxiety-like behavior in the OFT relative to their wild-type littermates. However, such increase was not observed in elevated plus maze. For male mice, no between-genotype differences were observed in both tests at the above two developmental stages. Our results suggest that GABAA(δ)R preferentially affects the anxiety-like behavior in OFT in a development-dependent manner, but only in female mice.
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43
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Lüscher B, Möhler H. Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience. F1000Res 2019; 8. [PMID: 31275559 PMCID: PMC6544078 DOI: 10.12688/f1000research.18758.1] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/22/2019] [Indexed: 12/18/2022] Open
Abstract
The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABA
A receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition. In addition, allopregnanolone may stabilize normal mood by decreasing the activity of stress-responsive dentate granule cells and thereby sustain resilience behavior. Therefore, allopregnanolone may augment and extend its antidepressant activity by fostering resilience. The recent structural resolution of the neurosteroid binding domain of GABA
A receptors will expedite the development of more selective ligands as a potential new class of central nervous system drugs.
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Affiliation(s)
- Bernhard Lüscher
- Department of Biology and Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, 16802, USA.,Center for Molecular Investigation of Neurological Disorders, The Huck Institutes for the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA
| | - Hanns Möhler
- Institute of Pharmacology and Neuroscience Center, University of Zurich, Zurich, 8057, Switzerland.,Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Zurich, 8057, Switzerland
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44
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Zhang CQ, McMahon B, Dong H, Warner T, Shen W, Gallagher M, Macdonald RL, Kang JQ. Molecular basis for and chemogenetic modulation of comorbidities in GABRG2-deficient epilepsies. Epilepsia 2019; 60:1137-1149. [PMID: 31087664 DOI: 10.1111/epi.15160] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 04/15/2019] [Accepted: 04/15/2019] [Indexed: 12/30/2022]
Abstract
OBJECTIVE γ-Aminobutyric acid type A (GABAA ) receptor subunit gene mutations are significant causes of epilepsy, which are often accompanied by various neuropsychiatric comorbidities, but the underlying mechanisms are unclear. It has been suggested that the comorbidities are caused by seizures, as the comorbidities often present in severe epilepsy syndromes. However, findings from both humans and animal models argue against this conclusion. Mutations in the GABAA receptor γ2 subunit gene GABRG2 have been associated with anxiety alone or with severe epilepsy syndromes and comorbid anxiety, suggesting that a core molecular defect gives rise to the phenotypic spectrum. Here, we determined the pathophysiology of comorbid anxiety in GABRG2 loss-of-function epilepsy syndromes, identified the central nucleus of the amygdala (CeA) as a primary site for epilepsy comorbid anxiety, and demonstrated a potential rescue of comorbid anxiety via neuromodulation of CeA neurons. METHODS We used brain slice recordings, subcellular fractionation with Western blot, immunohistochemistry, confocal microscopy, and a battery of behavior tests in combination with a chemogenetic approach to characterize anxiety and its underlying mechanisms in a Gabrg2+/Q390X knockin mouse and a Gabrg2+/- knockout mouse, each associated with a different epilepsy syndrome. RESULTS We found that impaired GABAergic neurotransmission in CeA underlies anxiety in epilepsy, which is due to reduced GABAA receptor subunit expression resulting from the mutations. Impaired GABAA receptor expression reduced GABAergic neurotransmission in CeA, but not in basolateral amygdala. Activation or inactivation of inhibitory neurons using a chemogenetic approach in CeA alone modulated anxietylike behaviors. Similarly, pharmacological enhancement of GABAergic signaling via γ2 subunit-containing receptors relieved the anxiety. SIGNIFICANCE Together, these data demonstrate the molecular basis for a comorbidity of epilepsy, anxiety, and suggest that impaired GABAA receptor function in CeA due to a loss-of-function mutation could at least contribute to anxiety. Modulation of CeA neurons could cause or suppress anxiety, suggesting a potential use of CeA neurons as therapeutic targets for treatment of anxiety in addition to traditional pharmacological approaches.
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Affiliation(s)
- Chun-Qing Zhang
- Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Neurosurgery, Xinqiao Hospital, Army Military Medical University, Chongqing, China
| | - Bryan McMahon
- Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Huancheng Dong
- Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Timothy Warner
- Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Wangzhen Shen
- Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Martin Gallagher
- Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Robert L Macdonald
- Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.,Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jing-Qiong Kang
- Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.,Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, Tennessee
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45
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Kwakowsky A, Calvo-Flores Guzmán B, Pandya M, Turner C, Waldvogel HJ, Faull RL. GABA A receptor subunit expression changes in the human Alzheimer's disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus. J Neurochem 2019; 145:374-392. [PMID: 29485232 DOI: 10.1111/jnc.14325] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 01/17/2018] [Accepted: 02/12/2018] [Indexed: 12/14/2022]
Abstract
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA type A receptors (GABAA Rs) are severely affected in Alzheimer's disease (AD). However, the distribution and subunit composition of GABAA Rs in the AD brain are not well understood. This is the first comprehensive study to show brain region- and cell layer-specific alterations in the expression of the GABAA R subunits α1-3, α5, β1-3 and γ2 in the human AD hippocampus, entorhinal cortex and superior temporal gyrus. In late-stage AD tissue samples using immunohistochemistry we found significant alteration of all investigated GABAA Rs subunits except for α3 and β1 that were well preserved. The most prominent changes include an increase in GABAA R α1 expression associated with AD in all layers of the CA3 region, in the stratum (str.) granulare and hilus of the dentate gyrus. We found a significant increase in GABAA R α2 expression in the str. oriens of the CA1-3, str. radiatum of the CA2,3 and decrease in the str. pyramidale of the CA1 region in AD cases. In AD there was a significant increase in GABAA R α5 subunit expression in str. pyramidale, str. oriens of the CA1 region and decrease in the superior temporal gyrus. We also found a significant decrease in the GABAA R β3 subunit immunoreactivity in the str. oriens of the CA2, str. granulare and str. moleculare of the dentate gyrus. In conclusion, these findings indicate that the expression of the GABAA R subunits shows brain region- and layer-specific alterations in AD, and these changes could significantly influence and alter GABAA R function in the disease. Cover Image for this issue: doi: 10.1111/jnc.14179.
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Affiliation(s)
- Andrea Kwakowsky
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Beatriz Calvo-Flores Guzmán
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Madhavi Pandya
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Clinton Turner
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.,Department of Anatomical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand
| | - Henry J Waldvogel
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Richard L Faull
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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46
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Lorenz-Guertin JM, Bambino MJ, Das S, Weintraub ST, Jacob TC. Diazepam Accelerates GABA AR Synaptic Exchange and Alters Intracellular Trafficking. Front Cell Neurosci 2019; 13:163. [PMID: 31080408 PMCID: PMC6497791 DOI: 10.3389/fncel.2019.00163] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 04/08/2019] [Indexed: 12/21/2022] Open
Abstract
Despite 50+ years of clinical use as anxiolytics, anti-convulsants, and sedative/hypnotic agents, the mechanisms underlying benzodiazepine (BZD) tolerance are poorly understood. BZDs potentiate the actions of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, through positive allosteric modulation of γ2 subunit containing GABA type A receptors (GABAARs). Here we define key molecular events impacting γ2 GABAAR and the inhibitory synapse gephyrin scaffold following initial sustained BZD exposure in vitro and in vivo. Using immunofluorescence and biochemical experiments, we found that cultured cortical neurons treated with the classical BZD, diazepam (DZP), presented no substantial change in surface or synaptic levels of γ2-GABAARs. In contrast, both γ2 and the postsynaptic scaffolding protein gephyrin showed diminished total protein levels following a single DZP treatment in vitro and in mouse cortical tissue. We further identified DZP treatment enhanced phosphorylation of gephyrin Ser270 and increased generation of gephyrin cleavage products. Selective immunoprecipitation of γ2 from cultured neurons revealed enhanced ubiquitination of this subunit following DZP exposure. To assess novel trafficking responses induced by DZP, we employed a γ2 subunit containing an N terminal fluorogen-activating peptide (FAP) and pH-sensitive green fluorescent protein (γ2pHFAP). Live-imaging experiments using γ2pHFAP GABAAR expressing neurons identified enhanced lysosomal targeting of surface GABAARs and increased overall accumulation in vesicular compartments in response to DZP. Using fluorescence resonance energy transfer (FRET) measurements between α2 and γ2 subunits within a GABAAR in neurons, we identified reductions in synaptic clusters of this subpopulation of surface BZD sensitive receptor. Additional time-series experiments revealed the gephyrin regulating kinase ERK was inactivated by DZP at multiple time points. Moreover, we found DZP simultaneously enhanced synaptic exchange of both γ2-GABAARs and gephyrin using fluorescence recovery after photobleaching (FRAP) techniques. Finally we provide the first proteomic analysis of the BZD sensitive GABAAR interactome in DZP vs. vehicle treated mice. Collectively, our results indicate DZP exposure elicits down-regulation of gephyrin scaffolding and BZD sensitive GABAAR synaptic availability via multiple dynamic trafficking processes.
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Affiliation(s)
- Joshua M. Lorenz-Guertin
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Matthew J. Bambino
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Sabyasachi Das
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Susan T. Weintraub
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Tija C. Jacob
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
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47
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Cohen K, Weizman A, Weinstein A. Modulatory effects of cannabinoids on brain neurotransmission. Eur J Neurosci 2019; 50:2322-2345. [DOI: 10.1111/ejn.14407] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 03/06/2019] [Accepted: 03/08/2019] [Indexed: 12/31/2022]
Affiliation(s)
- Koby Cohen
- Department of Behavioral Science Ariel University Science Park 40700 Ariel Israel
| | | | - Aviv Weinstein
- Department of Behavioral Science Ariel University Science Park 40700 Ariel Israel
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48
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Waldvogel H, Biggins F, Singh A, Arasaratnam C, Faull R. Variable colocalisation of GABAA receptor subunits and glycine receptors on neurons in the human hypoglossal nucleus. J Chem Neuroanat 2019; 97:99-111. [DOI: 10.1016/j.jchemneu.2019.02.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 02/21/2019] [Accepted: 02/21/2019] [Indexed: 11/28/2022]
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49
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Fogaça MV, Duman RS. Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions. Front Cell Neurosci 2019. [PMID: 30914923 DOI: 10.3389/fncel.2019.00087/full] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
Major depressive disorder (MDD) is a debilitating illness characterized by neuroanatomical and functional alterations in limbic structures, notably the prefrontal cortex (PFC), that can be precipitated by exposure to chronic stress. For decades, the monoaminergic deficit hypothesis of depression provided the conceptual framework to understand the pathophysiology of MDD. However, accumulating evidence suggests that MDD and chronic stress are associated with an imbalance of excitation-inhibition (E:I) within the PFC, generated by a deficit of inhibitory synaptic transmission onto principal glutamatergic neurons. MDD patients and chronically stressed animals show a reduction in GABA and GAD67 levels in the brain, decreased expression of GABAergic interneuron markers, and alterations in GABAA and GABAB receptor levels. Moreover, genetically modified animals with deletion of specific GABA receptors subunits or interneuron function show depressive-like behaviors. Here, we provide further evidence supporting the role of cortical GABAergic interneurons, mainly somatostatin- and parvalbumin-expressing cells, required for the optimal E:I balance in the PFC and discuss how the malfunction of these cells can result in depression-related behaviors. Finally, considering the relatively low efficacy of current available medications, we review new fast-acting pharmacological approaches that target the GABAergic system to treat MDD. We conclude that deficits in cortical inhibitory neurotransmission and interneuron function resulting from chronic stress exposure can compromise the integrity of neurocircuits and result in the development of MDD and other stress-related disorders. Drugs that can establish a new E:I balance in the PFC by targeting the glutamatergic and GABAergic systems show promising as fast-acting antidepressants and represent breakthrough strategies for the treatment of depression.
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Affiliation(s)
- Manoela V Fogaça
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
| | - Ronald S Duman
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
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50
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Fogaça MV, Duman RS. Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions. Front Cell Neurosci 2019; 13:87. [PMID: 30914923 PMCID: PMC6422907 DOI: 10.3389/fncel.2019.00087] [Citation(s) in RCA: 235] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/20/2019] [Indexed: 12/14/2022] Open
Abstract
Major depressive disorder (MDD) is a debilitating illness characterized by neuroanatomical and functional alterations in limbic structures, notably the prefrontal cortex (PFC), that can be precipitated by exposure to chronic stress. For decades, the monoaminergic deficit hypothesis of depression provided the conceptual framework to understand the pathophysiology of MDD. However, accumulating evidence suggests that MDD and chronic stress are associated with an imbalance of excitation-inhibition (E:I) within the PFC, generated by a deficit of inhibitory synaptic transmission onto principal glutamatergic neurons. MDD patients and chronically stressed animals show a reduction in GABA and GAD67 levels in the brain, decreased expression of GABAergic interneuron markers, and alterations in GABAA and GABAB receptor levels. Moreover, genetically modified animals with deletion of specific GABA receptors subunits or interneuron function show depressive-like behaviors. Here, we provide further evidence supporting the role of cortical GABAergic interneurons, mainly somatostatin- and parvalbumin-expressing cells, required for the optimal E:I balance in the PFC and discuss how the malfunction of these cells can result in depression-related behaviors. Finally, considering the relatively low efficacy of current available medications, we review new fast-acting pharmacological approaches that target the GABAergic system to treat MDD. We conclude that deficits in cortical inhibitory neurotransmission and interneuron function resulting from chronic stress exposure can compromise the integrity of neurocircuits and result in the development of MDD and other stress-related disorders. Drugs that can establish a new E:I balance in the PFC by targeting the glutamatergic and GABAergic systems show promising as fast-acting antidepressants and represent breakthrough strategies for the treatment of depression.
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Affiliation(s)
- Manoela V Fogaça
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
| | - Ronald S Duman
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
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