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García-Gutiérrez MS, Navarro D, Torregrosa AB, Viudez-Martínez A, Giner S, Manzanares J. Alterations of BDNF, mGluR5, Homer1a, p11 and excitatory/inhibitory balance in corticolimbic brain regions of suicide decedents. J Affect Disord 2023; 339:366-376. [PMID: 37437733 DOI: 10.1016/j.jad.2023.07.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 06/02/2023] [Accepted: 07/08/2023] [Indexed: 07/14/2023]
Abstract
BACKGROUND Developing biological based approaches for preventing suicide has become a priority. In recent years, there has been a surge in studies investigating the role of the glutamatergic system in suicide, although it remains unclear. METHODS We evaluated changes in the gene expression of the metabotropic glutamate receptor 5 (mGluR5) and its scaffolding proteins Homer1a and p11 in the dorsolateral prefrontal cortex (DLPFC), amygdala (AMY), and hippocampus (HIP) of 28 suicide decedents (S) (with no clinical psychiatric history or treatment with anxiolytics or antidepressants) and 26 controls (C) by real-time PCR (qPCR). Indeed, we measured BDNF gene expression and VGluT1 and VGAT immunoreactivities in the HIP by qPCR and immunohistochemistry, respectively. Cases and controls matched for age (C: 48.6 ± 11.6 years; S: 46.9 ± 14.5 years) and postmortem interval (PMI; C: 20.1 ± 13h; S: 16.9 ± 5h). RESULTS In DLPFC, S had lower p11 gene expression levels, but no differences were found in mGluR5 or Homer1a. In the AMY and HIP, mGluR5 and Homer1a were increased, p11 and BDNF were reduced. In the HIP, there were less VGAT-ir and more VGluT1-ir. LIMITATIONS Future studies are necessary to evaluate protein levels, and determine the cell types and potential compensatory mechanisms in a larger sample including S diagnosed with psychiatric disorders, females and different ethnicities. CONCLUSIONS This study identified significant alterations in mGluR5, Homer1a, p11, BDNF and excitatory/inhibitory balance in corticolimbic brain areas of S. These results further characterize the biological basis of suicide, contributing to the identification of potential biomarkers for suicide prevention.
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Affiliation(s)
- María S García-Gutiérrez
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante 03550, Alicante, Spain; Red de Investigación en Atención Primaria de Adicciones, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain
| | - Daniela Navarro
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante 03550, Alicante, Spain; Red de Investigación en Atención Primaria de Adicciones, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain
| | - Abraham B Torregrosa
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante 03550, Alicante, Spain; Red de Investigación en Atención Primaria de Adicciones, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain
| | | | - Salvador Giner
- Instituto de Medicina Legal, Avenida Aguilera 53, 03007, Alicante, Spain
| | - Jorge Manzanares
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante 03550, Alicante, Spain; Red de Investigación en Atención Primaria de Adicciones, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain.
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Calpe-López C, Martínez-Caballero MÁ, García-Pardo MP, Aguilar MA. Resilience to the short- and long-term behavioral effects of intermittent repeated social defeat in adolescent male mice. Pharmacol Biochem Behav 2023:173574. [PMID: 37315696 DOI: 10.1016/j.pbb.2023.173574] [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: 02/27/2023] [Revised: 05/16/2023] [Accepted: 06/03/2023] [Indexed: 06/16/2023]
Abstract
BACKGROUND Exposure to intermittent repeated social defeat (IRSD) increases the sensitivity of mice to the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. Some animals are resilient to this effect of IRSD, though research exploring this inconsistency in adolescent mice is scarce. Thus, our aim was to characterize the behavioral profile of mice exposed to IRSD during early adolescence and to explore a potential association with resilience to the short- and long-term effects of IRSD. METHODS Thirty-six male C57BL/6 mice were exposed to IRSD during early adolescence (PND 27, 30, 33 and 36), while another 10 male mice did not undergo stress (controls). Defeated mice and controls then carried out the following battery of behavioral tests; the Elevated Plus Maze, Hole-Board and Social Interaction Test on PND 37, and the Tail Suspension and Splash tests on PND 38. Three weeks later, all the mice were submitted to the CPP paradigm with a low dose of cocaine (1.5 mg/kg). RESULTS IRSD during early adolescence induced depressive-like behavior in the Social Interaction and Splash tests and increased the rewarding effects of cocaine. Mice with low levels of submissive behavior during episodes of defeat were resilient to the short- and long-term effects of IRSD. In addition, resilience to the short-term effects of IRSD on social interaction and grooming behavior predicted resilience to the long-term effects of IRSD on cocaine reward. CONCLUSION Our findings help to characterize the nature of resilience to the effects of social stress during adolescence.
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Affiliation(s)
- Claudia Calpe-López
- Neurobehavioural Mechanisms and Endophenotypes of Addictive Behavior Research Unit, Department of Psychobiology, University of Valencia, Valencia, Spain
| | - Maria Ángeles Martínez-Caballero
- Neurobehavioural Mechanisms and Endophenotypes of Addictive Behavior Research Unit, Department of Psychobiology, University of Valencia, Valencia, Spain
| | - Maria Pilar García-Pardo
- Department of Psychology and Sociology, Faculty of Social Sciences, University of Zaragoza, Teruel, Spain
| | - Maria Asunción Aguilar
- Neurobehavioural Mechanisms and Endophenotypes of Addictive Behavior Research Unit, Department of Psychobiology, University of Valencia, Valencia, Spain.
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Khairuddin S, Lim WL, Aquili L, Tsui KC, Tse ACK, Jayalath S, Varma R, Sharp T, Benazzouz A, Steinbusch H, Blokland A, Temel Y, Lim LW. Prelimbic Cortical Stimulation Induces Antidepressant-like Responses through Dopaminergic-Dependent and -Independent Mechanisms. Cells 2023; 12:1449. [PMID: 37296570 PMCID: PMC10253143 DOI: 10.3390/cells12111449] [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: 04/05/2023] [Revised: 05/16/2023] [Accepted: 05/18/2023] [Indexed: 06/12/2023] Open
Abstract
High-frequency stimulation (HFS) is a promising therapy for patients with depression. However, the mechanisms underlying the HFS-induced antidepressant-like effects on susceptibility and resilience to depressive-like behaviors remain obscure. Given that dopaminergic neurotransmission has been found to be disrupted in depression, we investigated the dopamine(DA)-dependent mechanism of the antidepressant-like effects of HFS of the prelimbic cortex (HFS PrL). We performed HFS PrL in a rat model of mild chronic unpredictable stress (CUS) together with 6-hydroxydopamine lesioning in the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA). Animals were assessed for anxiety, anhedonia, and behavioral despair. We also examined levels of corticosterone, hippocampal neurotransmitters, neuroplasticity-related proteins, and morphological changes in dopaminergic neurons. We found 54.3% of CUS animals exhibited decreased sucrose consumption and were designated as CUS-susceptible, while the others were designated CUS-resilient. HFS PrL in both the CUS-susceptible and CUS-resilient animals significantly increased hedonia, reduced anxiety, decreased forced swim immobility, enhanced hippocampal DA and serotonin levels, and reduced corticosterone levels when compared with the respective sham groups. The hedonic-like effects were abolished in both DRN- and VTA-lesioned groups, suggesting the effects of HFS PrL are DA-dependent. Interestingly, VTA-lesioned sham animals had increased anxiety and forced swim immobility, which was reversed by HFS PrL. The VTA-lesioned HFS PrL animals also had elevated DA levels, and reduced p-p38 MAPK and NF-κB levels when compared to VTA-lesioned sham animals. These findings suggest that HFS PrL in stressed animals leads to profound antidepressant-like responses possibly through both DA-dependent and -independent mechanisms.
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Affiliation(s)
- Sharafuddin Khairuddin
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wei Ling Lim
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Biological Sciences, Sunway University, Bandar Sunway, Petaling Jaya 47500, Malaysia
| | - Luca Aquili
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Discipline of Psychology, College of Health and Education, Murdoch University, Perth 6150, Australia
| | - Ka Chun Tsui
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Anna Chung-Kwan Tse
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Shehani Jayalath
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ruhani Varma
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Trevor Sharp
- Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK
| | - Abdelhamid Benazzouz
- CNRS UMR5293, Institute of Neurodegenerative Diseases, University de Bordeaux, 33000 Bordeaux, France
| | - Harry Steinbusch
- Department of Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Arjan Blokland
- Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Yasin Temel
- Department of Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands
- Department of Neurosurgery, Maastricht University, 6229 HX Maastricht, The Netherlands
| | - Lee Wei Lim
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Biological Sciences, Sunway University, Bandar Sunway, Petaling Jaya 47500, Malaysia
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4
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Thompson SM. Plasticity of synapses and reward circuit function in the genesis and treatment of depression. Neuropsychopharmacology 2023; 48:90-103. [PMID: 36057649 PMCID: PMC9700729 DOI: 10.1038/s41386-022-01422-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/18/2022] [Accepted: 08/01/2022] [Indexed: 11/08/2022]
Abstract
What changes in brain function cause the debilitating symptoms of depression? Can we use the answers to this question to invent more effective, faster acting antidepressant drug therapies? This review provides an overview and update of the converging human and preclinical evidence supporting the hypothesis that changes in the function of excitatory synapses impair the function of the circuits they are embedded in to give rise to the pathological changes in mood, hedonic state, and thought processes that characterize depression. The review also highlights complementary human and preclinical findings that classical and novel antidepressant drugs relieve the symptoms of depression by restoring the functions of these same synapses and circuits. These findings offer a useful path forward for designing better antidepressant compounds.
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Affiliation(s)
- Scott M Thompson
- Department of Psychiatry, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, 80045, CO, USA.
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Suzuki A, Hara H, Kimura H. Role of the AMPA receptor in antidepressant effects of ketamine and potential of AMPA receptor potentiators as a novel antidepressant. Neuropharmacology 2023; 222:109308. [PMID: 36341809 DOI: 10.1016/j.neuropharm.2022.109308] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022]
Abstract
Ketamine exerts rapid and long-lasting antidepressant effects in patients with treatment-resistant depression. However, its clinical use is limited by its undesirable psychotomimetic side effects. Accumulating evidence from preclinical studies has shown that the antidepressant effects of ketamine are dependent on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) activation, which triggers activation of the mechanistic target of rapamycin pathway and brain-derived neurotrophic factor release. Thus, AMPA-R has emerged as a promising new target for novel antidepressants with a rapid onset of action. However, almost all known AMPA-R potentiators carry the risk of a narrow bell-shaped dose-response curve and a poor safety margin against seizures. Our data suggest that agonistic activity is not only related to the risks of bell-shaped dose-response curves and seizures but also to the reduced synaptic transmission and procognitive effects of AMPA-R potentiators. In this review, we describe our original screening approach that led to the discovery of an investigational AMPA-R potentiator with low agonistic activity, TAK-653. We further review the in vitro and in vivo profiles of TAK-653, including its procognitive and antidepressant-like effects, as well as its safety profile, in comparison with known AMPA-R potentiators with agonistic activity and AMPA, an AMPA-R agonist. The low agnostic activity of TAK-653 may overcome limitations of known AMPA-R potentiators. This article is part of the Special Issue on 'Ketamine and its Metabolites'.
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Affiliation(s)
- Atsushi Suzuki
- Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan
| | - Hiroe Hara
- Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan
| | - Haruhide Kimura
- Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.
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6
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Grossman YS, Fillinger C, Manganaro A, Voren G, Waldman R, Zou T, Janssen WG, Kenny PJ, Dumitriu D. Structure and function differences in the prelimbic cortex to basolateral amygdala circuit mediate trait vulnerability in a novel model of acute social defeat stress in male mice. Neuropsychopharmacology 2022; 47:788-799. [PMID: 34799681 PMCID: PMC8782864 DOI: 10.1038/s41386-021-01229-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/22/2021] [Accepted: 10/30/2021] [Indexed: 02/03/2023]
Abstract
Stressful life events are ubiquitous and well-known to negatively impact mental health. However, in both humans and animal models, there is large individual variability in how individuals respond to stress, with some but not all experiencing long-term adverse consequences. While there is growing understanding of the neurobiological underpinnings of the stress response, much less is known about how neurocircuits shaped by lifetime experiences are activated during an initial stressor and contribute to this selective vulnerability versus resilience. We developed a model of acute social defeat stress (ASDS) that allows classification of male mice into "susceptible" (socially avoidant) versus "resilient" (expressing control-level social approach) one hour after exposure to six minutes of social stress. Using circuit tracing and high-resolution confocal imaging, we explored differences in activation and dendritic spine density and morphology in the prelimbic cortex to basolateral amygdala (PL→BLA) circuit in resilient versus susceptible mice. Susceptible mice had greater PL→BLA recruitment during ASDS and activated PL→BLA neurons from susceptible mice had more and larger mushroom spines compared to resilient mice. We hypothesized identified structure/function differences indicate an overactive PL→BLA response in susceptible mice and used an intersectional chemogenetic approach to inhibit the PL→BLA circuit during or prior to ASDS. We found in both cases that this blocked ASDS-induced social avoidance. Overall, we show PL→BLA structure/function differences mediate divergent behavioral responses to ASDS in male mice. These results support PL→BLA circuit overactivity during stress as a biomarker of trait vulnerability and potential target for prevention of stress-induced psychopathology.
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Affiliation(s)
- Yael S Grossman
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Duke University School of Medicine, Durham, NC, USA
| | - Clementine Fillinger
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alessia Manganaro
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
| | - George Voren
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rachel Waldman
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tiffany Zou
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - William G Janssen
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Paul J Kenny
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dani Dumitriu
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Environmental Medicine & Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA.
- New York State Psychiatric Institute, Columbia University, New York, NY, USA.
- Sackler Institute, Columbia University, New York, NY, USA.
- Columbia Population Research Center, Columbia University, New York, NY, USA.
- Zuckerman Institute, Columbia University, New York, NY, USA.
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7
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Calpe-López C, Martínez-Caballero MA, García-Pardo MP, Aguilar MA. Resilience to the effects of social stress on vulnerability to developing drug addiction. World J Psychiatry 2022; 12:24-58. [PMID: 35111578 PMCID: PMC8783163 DOI: 10.5498/wjp.v12.i1.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/01/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.
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Affiliation(s)
| | | | - Maria P García-Pardo
- Faculty of Social and Human Sciences, University of Zaragoza, Teruel 44003, Spain
| | - Maria A Aguilar
- Department of Psychobiology, University of Valencia, Valencia 46010, Spain
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Kadriu B, Musazzi L, Johnston JN, Kalynchuk LE, Caruncho HJ, Popoli M, Zarate CA. Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road. Drug Discov Today 2021; 26:2816-2838. [PMID: 34358693 DOI: 10.1016/j.drudis.2021.07.027] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/12/2021] [Accepted: 07/28/2021] [Indexed: 12/13/2022]
Abstract
Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) signaling has spurred a resurgence of interest in the field. This review explores agents in various stages of development for neuropsychiatric disorders that positively modulate AMPARs, both directly and indirectly. Despite promising preclinical research, few direct and indirect AMPAR positive modulators have progressed past early clinical development. Challenges such as low potency have created barriers to effective implementation. Nevertheless, the functional complexity of AMPARs sets them apart from other drug targets and allows for specificity in drug discovery. Additional effective treatments for neuropsychiatric disorders that work through positive AMPAR modulation may eventually be developed.
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Affiliation(s)
- Bashkim Kadriu
- Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
| | - Laura Musazzi
- School of Medicine and Surgery, University of Milano-Bicocca, Italy
| | - Jenessa N Johnston
- Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA; Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Lisa E Kalynchuk
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Hector J Caruncho
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Maurizio Popoli
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Italy
| | - Carlos A Zarate
- Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
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9
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Targeting the dysfunction of glutamate receptors for the development of novel antidepressants. Pharmacol Ther 2021; 226:107875. [PMID: 33901503 DOI: 10.1016/j.pharmthera.2021.107875] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2021] [Indexed: 12/19/2022]
Abstract
Increasing evidence indicates that dysfunction of glutamate receptors is involved in the pathophysiology of major depressive disorder (MDD). Although accumulating efforts have been made to elucidate the applications and mechanisms underlying antidepressant-like effects of ketamine, a non-selective antagonist of N-methyl-d-aspartate receptor (NMDAR), the role of specific glutamate receptor subunit in regulating depression is not completely clear. The current review aims to discuss the relationships between glutamate receptor subunits and depressive-like behaviors. Research literatures were searched from inception to July 2020. We summarized the alterations of glutamate receptor subunits in patients with MDD and animal models of depression. Animal behaviors in response to dysfunction of glutamate receptor subunits were also surveyed. To fully understand mechanisms underlying antidepressant-like effects of modulators targeting glutamate receptors, we discussed effects of each glutamate receptor subunit on serotonin system, synaptic plasticity, neurogenesis and neuroinflammation. Finally, we collected most recent clinical applications of glutamate receptor modulators and pointed out the limitations of these candidates in the treatment of MDD.
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Oligophrenin-1 moderates behavioral responses to stress by regulating parvalbumin interneuron activity in the medial prefrontal cortex. Neuron 2021; 109:1636-1656.e8. [PMID: 33831348 DOI: 10.1016/j.neuron.2021.03.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 02/09/2021] [Accepted: 03/10/2021] [Indexed: 12/28/2022]
Abstract
Ample evidence indicates that individuals with intellectual disability (ID) are at increased risk of developing stress-related behavioral problems and mood disorders, yet a mechanistic explanation for such a link remains largely elusive. Here, we focused on characterizing the syndromic ID gene oligophrenin-1 (OPHN1). We find that Ophn1 deficiency in mice markedly enhances helpless/depressive-like behavior in the face of repeated/uncontrollable stress. Strikingly, Ophn1 deletion exclusively in parvalbumin (PV) interneurons in the prelimbic medial prefrontal cortex (PL-mPFC) is sufficient to induce helplessness. This behavioral phenotype is mediated by a diminished excitatory drive onto Ophn1-deficient PL-mPFC PV interneurons, leading to hyperactivity in this region. Importantly, suppressing neuronal activity or RhoA/Rho-kinase signaling in the PL-mPFC reverses helpless behavior. Our results identify OPHN1 as a critical regulator of adaptive behavioral responses to stress and shed light onto the mechanistic links among OPHN1 genetic deficits, mPFC circuit dysfunction, and abnormalities in stress-related behaviors.
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Photobiomodulation Therapy Ameliorates Glutamatergic Dysfunction in Mice with Chronic Unpredictable Mild Stress-Induced Depression. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6678276. [PMID: 33859781 PMCID: PMC8024102 DOI: 10.1155/2021/6678276] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/02/2021] [Accepted: 03/16/2021] [Indexed: 12/28/2022]
Abstract
Accumulating evidence indicates that dysfunction of the glutamatergic neurotransmission has been widely involved in the pathophysiology and treatment of depression. Photobiomodulation therapy (PBMT) has been demonstrated to regulate neuronal function both in vitro and in vivo. Herein, we aim to investigate whether the antidepressant phenotype of PBMT is associated with the improvement of glutamatergic dysfunction and to explore the mechanisms involved. Results showed that PBMT decreased extracellular glutamate levels via upregulation of glutamate transporter-1 (GLT-1) and rescued astrocyte loss in the cerebral cortex and hippocampus, which also alleviated dendritic atrophy and upregulated the expression of AMPA receptors on the postsynaptic membrane, ultimately exhibiting behaviorally significant antidepressant effects in mice exposed to chronic unpredictable mild stress (CUMS). Notably, PBMT also obtained similar antidepressant effects in a depressive mouse model subcutaneously injected with corticosterone (CORT). Evidence from in vitro mechanistic experiments demonstrated that PBMT treatment significantly increased both the GLT-1 mRNA and protein levels via the Akt/NF-κB signaling pathway. NF-κB-regulated transcription was in an Akt-dependent manner, while inhibition of Akt attenuated the DNA-binding efficiency of NF-κB to the GLT-1 promoter. Importantly, in vitro, we further found that PKA activation was responsible for phosphorylation and surface levels of AMPA receptors induced by PBMT, which is likely to rescue excitatory synaptic transmission. Taken together, our research suggests that PBMT as a feasible therapeutic approach has great potential value to control the progression of depression.
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Trujillo-Villarreal LA, Romero-Díaz VJ, Marino-Martínez IA, Fuentes-Mera L, Ponce-Camacho MA, Devenyi GA, Mallar Chakravarty M, Camacho-Morales A, Garza-Villarreal EE. Maternal cafeteria diet exposure primes depression-like behavior in the offspring evoking lower brain volume related to changes in synaptic terminals and gliosis. Transl Psychiatry 2021; 11:53. [PMID: 33446642 PMCID: PMC7809040 DOI: 10.1038/s41398-020-01157-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
Maternal nutritional programming by caloric exposure during pregnancy and lactation results in long-term behavioral modification in the offspring. Here, we characterized the effect of maternal caloric exposure on synaptic and brain morphological organization and its effects on depression-like behavior susceptibility in rats' offspring. Female Wistar rats were exposed to chow or cafeteria (CAF) diet for 9 weeks (pre-pregnancy, pregnancy, and lactation) and then switched to chow diet after weaning. By postnatal day 60, the male Wistar rat offspring were tested for depressive-like behavior using operational conditioning, novelty suppressed feeding, sucrose preference, and open-field test. Brain macro and microstructural morphology were analyzed using magnetic resonance imaging deformation-based morphometry (DBM) and western blot, immunohistochemistry for NMDA and AMPA receptor, synaptophysin and myelin, respectively. We found that the offspring of mothers exposed to CAF diet displayed deficient motivation showing decrease in the operant conditioning, sucrose preference, and suppressed feeding test. Macrostructural DBM analysis showed reduction in the frontomesocorticolimbic circuit volume including the nucleus accumbens (NAc), hippocampus, and prefrontal cortex. Microstructural analysis revealed reduced synaptic terminals in hippocampus and NAc, whereas increased glial fibrillary acidic protein in hippocampus and lateral hypothalamus, as well as a decrease in the hippocampal cell number and myelin reduction in the dentate gyrus and hilus, respectively. Also, offspring exhibited increase of the GluR1 and GLUR2 subunits of AMPA receptor, whereas a decrease in the mGluR2 expression in hippocampus. Our findings reveal that maternal programming might prime depression-like behavior in the offspring by modulating macro and micro brain organization of the frontomesocorticolimbic circuit.
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Affiliation(s)
- Luis A Trujillo-Villarreal
- Department of Biochemistry, College of Medicine, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, NL, México
- Neurometabolism Unit, Center for Research and Development in Health Sciences, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, NL, México
| | - Viktor J Romero-Díaz
- Gene therapy Unit, Center for Research and Development in Health Sciences, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, NL, México
| | - Iván Alberto Marino-Martínez
- Gene therapy Unit, Center for Research and Development in Health Sciences, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, NL, México
| | - Lizeth Fuentes-Mera
- Department of Biochemistry, College of Medicine, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, NL, México
| | - Marco Antonio Ponce-Camacho
- Servicio de Anatomía Patológica y Citopatología. Hospital Universitario Dr José Eleuterio González, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, NL, México
| | - Gabriel A Devenyi
- Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, QC, Canada
| | - M Mallar Chakravarty
- Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, QC, Canada
- Department of Psychiatry, McGill University, Montreal, QC, Canada
- Department of Biological and Biomedical Engineering, McGill University, Montreal, Canada
| | - Alberto Camacho-Morales
- Department of Biochemistry, College of Medicine, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, NL, México.
- Neurometabolism Unit, Center for Research and Development in Health Sciences, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, NL, México.
| | - Eduardo E Garza-Villarreal
- Instituto de Neurobiología, Universidad Nacional Autónoma de México campus Juriquilla, Queretaro, Mexico.
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Tse YC, Lopez J, Moquin A, Wong SMA, Maysinger D, Wong TP. The susceptibility to chronic social defeat stress is related to low hippocampal extrasynaptic NMDA receptor function. Neuropsychopharmacology 2019; 44:1310-1318. [PMID: 30723288 PMCID: PMC6785155 DOI: 10.1038/s41386-019-0325-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 01/16/2019] [Accepted: 01/19/2019] [Indexed: 12/15/2022]
Abstract
N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety- and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystine-glutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.
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Affiliation(s)
- Yiu Chung Tse
- 0000 0001 2353 5268grid.412078.8Douglas Mental Health University Institute, 6875 LaSalle Blvd, Montreal, QC Canada
| | - Joëlle Lopez
- 0000 0001 2353 5268grid.412078.8Douglas Mental Health University Institute, 6875 LaSalle Blvd, Montreal, QC Canada
| | - Alexandre Moquin
- 0000 0004 1936 8649grid.14709.3bDepartment of Pharmacology & Therapeutics, McGill University, Montreal, QC Canada
| | - Shui-Ming Alice Wong
- 0000 0001 2353 5268grid.412078.8Douglas Mental Health University Institute, 6875 LaSalle Blvd, Montreal, QC Canada
| | - Dusica Maysinger
- 0000 0004 1936 8649grid.14709.3bDepartment of Pharmacology & Therapeutics, McGill University, Montreal, QC Canada
| | - Tak Pan Wong
- Douglas Mental Health University Institute, 6875 LaSalle Blvd, Montreal, QC, Canada. .,Department of Psychiatry, McGill University, Montreal, QC, Canada.
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Alaiyed S, Conant K. A Role for Matrix Metalloproteases in Antidepressant Efficacy. Front Mol Neurosci 2019; 12:117. [PMID: 31133801 PMCID: PMC6517485 DOI: 10.3389/fnmol.2019.00117] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 04/24/2019] [Indexed: 01/10/2023] Open
Abstract
Major depressive disorder is a debilitating condition that affects approximately 15% of the United States population. Though the neurophysiological mechanisms that underlie this disorder are not completely understood, both human and rodent studies suggest that excitatory/inhibitory (E/I) balance is reduced with the depressive phenotype. In contrast, antidepressant efficacy in responsive individuals correlates with increased excitatory neurotransmission in select brain regions, suggesting that the restoration of E/I balance may improve mood. Enhanced excitatory transmission can occur through mechanisms including increased dendritic arborization and synapse formation in pyramidal neurons. Reduced activity of inhibitory neurons may also contribute to antidepressant efficacy. Consistent with this possibility, the fast-acting antidepressant ketamine may act by selective inhibition of glutamatergic input to GABA releasing parvalbumin (PV)-expressing interneurons. Recent work has also shown that a negative allosteric modulator of the GABA-A receptor α subunit can improve depression-related behavior. PV-expressing interneurons are thought to represent critical pacemakers for synchronous network events. These neurons also represent the predominant GABAergic neuronal population that is enveloped by the perineuronal net (PNN), a lattice-like structure that is thought to stabilize glutamatergic input to this cell type. Disruption of the PNN reduces PV excitability and increases pyramidal cell excitability. Various antidepressant medications increase the expression of matrix metalloproteinases (MMPs), enzymes that can increase pyramidal cell dendritic arborization and spine formation. MMPs can also cleave PNN proteins to reduce PV neuron-mediated inhibition. The present review will focus on mechanisms that may underlie antidepressant efficacy, with a focus on monoamines as facilitators of increased matrix metalloprotease (MMP) expression and activation. Discussion will include MMP-dependent effects on pyramidal cell structure and function, as well as MMP-dependent effects on PV expressing interneurons. We conclude with discussion of antidepressant use for those at risk for Alzheimer’s disease, and we also highlight areas for further study.
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Affiliation(s)
- Seham Alaiyed
- Department of Pharmacology, Georgetown University Medical Center, Washington, DC, United States
| | - Katherine Conant
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United States
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Leem YH, Park JS, Chang H, Park J, Kim HS. Exercise Prevents Memory Consolidation Defects Via Enhancing Prolactin Responsiveness of CA1 Neurons in Mice Under Chronic Stress. Mol Neurobiol 2019; 56:6609-6625. [DOI: 10.1007/s12035-019-1560-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 03/13/2019] [Indexed: 12/21/2022]
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Réus GZ, de Moura AB, Silva RH, Resende WR, Quevedo J. Resilience Dysregulation in Major Depressive Disorder: Focus on Glutamatergic Imbalance and Microglial Activation. Curr Neuropharmacol 2018; 16:297-307. [PMID: 28676011 PMCID: PMC5843981 DOI: 10.2174/1570159x15666170630164715] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 06/05/2017] [Accepted: 06/22/2017] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Many studies have been shown an important role of glutamatergic system as well microglial activation in the pathophysiology of major depressive disorder (MDD). In humans most resistant to the development of psychiatric disorders, including MDD, are observed a greater degree of resilience resulting from stress. Less resilience is associated with neuroendocrine and neuroinflammatory markers, as well as with glutamatergic system dysregulation. Thus, this review we highlighted findings from literature identifying the function of glutamatergic system, microglial activation and inflammation in resilience. METHODS We conducted a review of computerized databases from 1970 to 2017. RESULTS There is an association between microglial activation and glutamatergic system activation with stress vulnerability and resilience. CONCLUSIONS Glutamate neurotransmission, including neurotransmitter synthesis, signalling, and glutamate receptor functions and expression all seem to be involved with both stress vulnerability and resilience. Moreover, inflammation and microglial activation mediate individual differences in resilience and the risk of stress-induced MDD.
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Affiliation(s)
- Gislaine Z. Réus
- Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Airam B. de Moura
- Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Ritele H. Silva
- Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Wilson R. Resende
- Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - João Quevedo
- Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
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Faye C, McGowan JC, Denny CA, David DJ. Neurobiological Mechanisms of Stress Resilience and Implications for the Aged Population. Curr Neuropharmacol 2018; 16:234-270. [PMID: 28820053 PMCID: PMC5843978 DOI: 10.2174/1570159x15666170818095105] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 06/25/2017] [Accepted: 07/27/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Stress is a common reaction to an environmental adversity, but a dysregulation of the stress response can lead to psychiatric illnesses such as major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and anxiety disorders. Yet, not all individuals exposed to stress will develop psychiatric disorders; those with enhanced stress resilience mechanisms have the ability to adapt successfully to stress without developing persistent psychopathology. Notably, the potential to enhance stress resilience in at-risk populations may prevent the onset of stress-induced psychiatric disorders. This novel idea has prompted a number of studies probing the mechanisms of stress resilience and how it can be manipulated. METHODS Here, we review the neurobiological factors underlying stress resilience, with particular focus on the serotoninergic (5-HT), glutamatergic, and γ-Aminobutyric acid (GABA) systems, as well as the hypothalamic-pituitary axis (HPA) in rodents and in humans. Finally, we discuss stress resiliency in the context of aging, as the likelihood of mood disorders increases in older adults. RESULTS Interestingly, increased resiliency has been shown to slow aging and improved overall health and quality of life. Research in the neurobiology of stress resilience, particularly throughout the aging process, is a nascent, yet, burgeoning field. CONCLUSION Overall, we consider the possible methods that may be used to induce resilient phenotypes, prophylactically in at-risk populations, such as in military personnel or in older MDD patients. Research in the mechanisms of stress resilience may not only elucidate novel targets for antidepressant treatments, but also provide novel insight about how to prevent these debilitating disorders from developing.
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Affiliation(s)
- Charlène Faye
- CESP/UMR-S 1178, Univ. Paris-Sud, Fac Pharmacie, Inserm, Université Paris-Saclay, 92296 Chatenay-Malabry, France
| | - Josephine C. McGowan
- Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, USA
| | - Christine A. Denny
- Department of Psychiatry, Columbia University, New York, NY, USA
- Division of Integrative Neuroscience, New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Inc., New York, NY, USA
| | - Denis J. David
- CESP/UMR-S 1178, Univ. Paris-Sud, Fac Pharmacie, Inserm, Université Paris-Saclay, 92296 Chatenay-Malabry, France
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Yim YS, Han W, Seo J, Kim CH, Kim DG. Differential mGluR5 expression in response to the same stress causes individually adapted hippocampal network activity. Biochem Biophys Res Commun 2018; 495:1305-1311. [DOI: 10.1016/j.bbrc.2017.11.172] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 11/27/2017] [Indexed: 10/18/2022]
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19
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Leem YH. The potential role of exercise in chronic stress-related changes in AMPA receptor phenotype underlying synaptic plasticity. J Exerc Nutrition Biochem 2017; 21:11-15. [PMID: 29370668 PMCID: PMC6373914 DOI: 10.20463/jenb.2017.0037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 12/31/2017] [Indexed: 11/26/2022] Open
Abstract
[Purpose] Chronic stress can cause disturbances in synaptic plasticity, such as longterm potentiation, along with behavioral defects including memory deficits. One major mechanism sustaining synaptic plasticity involves the dynamics and contents of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in the central nervous system. In particular, chronic stress-induced disruption of AMPARs includes it abnormal expression, trafficking, and calcium conductance at glutamatergic synapses, which contributes to synaptic plasticity at excitatory synapses. Exercise has the effect of promoting synaptic plasticity in neurons. However, the contribution of exercise to AMPAR behavior under chronic stressful maladaptation remains unclear. [Methods] The present article reviews the information about the chronic stress-related synaptic plasticity and the role of exercise from the previous-published articles. [Results] AMPAR-mediated synaptic transmission is an important for chronic stress-related changes of synaptic plasticity, and exercise may at least partly contribute to these episodes. [Conclusion] The present article discusses the relationship between AMPARs and synaptic plasticity in chronic stress, as well as the potential role of exercise.
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20
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Leem YH, Chang H. Arc/Arg3.1 protein expression in dorsal hippocampal CA1, a candidate event as a biomarker for the effects of exercise on chronic stress-evoked behavioral abnormalities. J Exerc Nutrition Biochem 2017; 21:45-51. [PMID: 29370673 PMCID: PMC5772070 DOI: 10.20463/jenb.2017.0033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 12/16/2017] [Indexed: 12/19/2022] Open
Abstract
[Purpose] Chronic stress is a risk factor for behavioral deficits, including impaired memory processing and depression. Exercise is well known to have beneficial impacts on brain health. [Methods] Mice were forced to treadmill running (4-week) during chronic restraint stress (6h/21d), and then behavioral tests were conducted by Novel object recognition, forced swimming test: FST, sociality test: SI. Dissected brain was stained with anti-calbindin-d28k and anti-Arc antibodies. Also, mice were treated with CX546 intraperitoneally during chronic restraint stress, and behavioral tests were assessed using Morris water maze, FST, and SI. Dissected brain was stained with anti-Arc antibody. [Results] The current study demonstrated that chronic stress-induced impairment of memory consolidation and depression-like behaviors, along with the changes in calbindin-d28k and Arc protein levels in the hippocampal CA1 area, were attenuated by regular treadmill running. Further, prolonged ampakine treatment prevented chronic stress-evoked behavioral abnormalities and nuclear Arc levels in hippocampal CA1 neurons. Nuclear localization of Arc protein in hippocampal CA1 neurons, but not total levels, was correlated with behavioral outcome in chronically stressed mice in response to a regular exercise regimen. [Conclusion] These results suggest that nuclear levels of Arc are strongly associated with behavioral changes, and highlight the role of exercise acting through an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR)-mediated mechanisms in a chronic stress-induced maladaptive condition.
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21
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Avila JA, Alliger AA, Carvajal B, Zanca RM, Serrano PA, Luine VN. Estradiol rapidly increases GluA2-mushroom spines and decreases GluA2-filopodia spines in hippocampus CA1. Hippocampus 2017; 27:1224-1229. [PMID: 28833901 PMCID: PMC5744887 DOI: 10.1002/hipo.22768] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/18/2017] [Accepted: 08/07/2017] [Indexed: 01/15/2023]
Abstract
Hippocampal dendritic spine density rapidly increases following estradiol (E2 ) treatment, but the types of spines and trafficking of synaptic markers have received little investigation. We assessed rapid effects of E2 over time on the density of four spine types (stubby, filopodial, long thin, and mushroom) and trafficking of AMPA receptor subunit GluA2 and PSD95 on tertiary, apical dendrites in CA1. Castrated male rats received 20 μg kg-1 of E2 or vehicle and were sacrificed 30 or 120 min later. Images of Golgi-Cox impregnated and PSD95/GluA2 stained dendrites were captured under the confocal microscope and quantified with IMARIS-XT. Stubby and filopodial spine densities did not change following treatment. Long-thin spines significantly decreased at 30 min while mushroom spines significantly increased at 120 min. GluA2, PSD95, and GluA2/PSD95 colocalization levels in stubby or long thin spines did not change, but filopodial spines had significantly reduced GluA2 levels at 30 min. Mushroom spines showed significantly increased levels for GluA2, PSD95 and GluA2/PSD95 colocalization at 120 min. Because GluA2 is important for memory consolidation, current results present novel data suggesting that trafficking of GluA2 to mushroom spines provides one mechanism contributing to estradiol's ability to enhance learning and memory by the PI3 signaling pathway.
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Affiliation(s)
- Jorge A Avila
- Department of Psychology, Hunter College, City University of New York, New York
- Behavioral and Cognitive Neuroscience Program, The Graduate Center of CUNY, New York, New York
| | - Amber A Alliger
- Department of Psychology, Hunter College, City University of New York, New York
| | - Brigett Carvajal
- Department of Psychology, Hunter College, City University of New York, New York
| | - Roseanna M Zanca
- Department of Psychology, Hunter College, City University of New York, New York
- Behavioral and Cognitive Neuroscience Program, The Graduate Center of CUNY, New York, New York
| | - Peter A Serrano
- Department of Psychology, Hunter College, City University of New York, New York
- Behavioral and Cognitive Neuroscience Program, The Graduate Center of CUNY, New York, New York
| | - Victoria N Luine
- Department of Psychology, Hunter College, City University of New York, New York
- Behavioral and Cognitive Neuroscience Program, The Graduate Center of CUNY, New York, New York
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Melatonin Augments the Effects of Fluoxetine on Depression-Like Behavior and Hippocampal BDNF-TrkB Signaling. Neurosci Bull 2017; 34:303-311. [PMID: 29086908 DOI: 10.1007/s12264-017-0189-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 09/14/2017] [Indexed: 12/23/2022] Open
Abstract
Depression is a debilitating psychiatric disorder with a huge socioeconomic burden, and its treatment relies on antidepressants including selective serotonin reuptake inhibitors (SSRIs). Recently, the melatonergic system that is closely associated with the serotonergic system has been implicated in the pathophysiology and treatment of depression. However, it remains unknown whether combined treatment with SSRI and melatonin has synergistic antidepressant effects. In this study, we applied a sub-chronic restraint stress paradigm, and evaluated the potential antidepressant effects of combined fluoxetine and melatonin in adult male mice. Sub-chronic restraint stress (6 h/day for 10 days) induced depression-like behavior as shown by deteriorated fur state, increased latency to groom in the splash test, and increased immobility time in the forced-swim test. Repeated administration of either fluoxetine or melatonin at 10 mg/kg during stress exposure failed to prevent depression-like phenotypes. However, combined treatment with fluoxetine and melatonin at the selected dose attenuated stress-induced behavioral abnormalities. Moreover, we found that the antidepressant effects of combined treatment were associated with the normalization of brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the hippocampus, but not in the prefrontal cortex. Our findings suggest that combined fluoxetine and melatonin treatment exerts synergistic antidepressant effects possibly by restoring hippocampal BDNF-TrkB signaling.
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Corticosteroid-induced dendrite loss and behavioral deficiencies can be blocked by activation of Abl2/Arg kinase. Mol Cell Neurosci 2017; 85:226-234. [PMID: 29107098 DOI: 10.1016/j.mcn.2017.10.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 10/25/2017] [Indexed: 12/31/2022] Open
Abstract
Stressor exposure induces neuronal remodeling in specific brain regions. Given the persistence of stress-related illnesses, key next steps in determining the contributions of neural structure to mental health are to identify cell types that fail to recover from stressor exposure and to identify "trigger points" and molecular underpinnings of stress-related neural degeneration. We evaluated dendrite arbor structure on hippocampal CA1 pyramidal neurons before, during, and following prolonged exposure to one key mediator of the stress response - corticosterone (cortisol in humans). Basal dendrite arbors progressively simplified during a 3-week exposure period, and failed to recover when corticosterone was withdrawn. Corticosterone exposure decreased levels of the dendrite stabilization factor Abl2/Arg nonreceptor tyrosine kinase and phosphorylation of its substrates p190RhoGAP and cortactin within 11days, suggesting that disruption of Arg-mediated signaling may trigger dendrite arbor atrophy and, potentially, behavioral abnormalities resulting from corticosterone exposure. To test this, we administered the novel, bioactive Arg kinase activator, 5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin, 5-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-2,4-imidazolidinedione (DPH), in conjunction with corticosterone. We found that repeated treatment corrected CA1 arbor structure, otherwise simplified by corticosterone. DPH also corrected corticosterone-induced errors in a hippocampal-dependent reversal learning task and anhedonic-like behavior. Thus, pharmacological compounds that target cytoskeletal regulators, rather than classical neurotransmitter systems, may interfere with stress-associated cognitive decline and mental health concerns.
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Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory. J Neurosci 2017; 36:11851-11864. [PMID: 27881773 DOI: 10.1523/jneurosci.1700-16.2016] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 09/15/2016] [Accepted: 09/20/2016] [Indexed: 11/21/2022] Open
Abstract
The insulin-regulated glucose transporter-4 (GluT4) is critical for insulin- and contractile-mediated glucose uptake in skeletal muscle. GluT4 is also expressed in some hippocampal neurons, but its functional role in the brain is unclear. Several established molecular modulators of memory processing regulate hippocampal GluT4 trafficking and hippocampal memory formation is limited by both glucose metabolism and insulin signaling. Therefore, we hypothesized that hippocampal GluT4 might be involved in memory processes. Here, we show that, in male rats, hippocampal GluT4 translocates to the plasma membrane after memory training and that acute, selective intrahippocampal inhibition of GluT4-mediated glucose transport impaired memory acquisition, but not memory retrieval. Other studies have shown that prolonged systemic GluT4 blockade causes insulin resistance. Unexpectedly, we found that prolonged hippocampal blockade of glucose transport through GluT4-upregulated markers of hippocampal insulin signaling prevented task-associated depletion of hippocampal glucose and enhanced both working and short-term memory while also impairing long-term memory. These effects were accompanied by increased expression of hippocampal AMPA GluR1 subunits and the neuronal GluT3, but decreased expression of hippocampal brain-derived neurotrophic factor, consistent with impaired ability to form long-term memories. Our findings are the first to show the cognitive impact of brain GluT4 modulation. They identify GluT4 as a key regulator of hippocampal memory processing and also suggest differential regulation of GluT4 in the hippocampus from that in peripheral tissues. SIGNIFICANCE STATEMENT The role of insulin-regulated glucose transporter-4 (GluT4) in the brain is unclear. In the current study, we demonstrate that GluT4 is a critical component of hippocampal memory processes. Memory training increased hippocampal GluT4 translocation and memory acquisition was impaired by GluT4 blockade. Unexpectedly, whereas long-term inhibition of GluT4 impaired long-term memory, short-term memory was enhanced. These data further our understanding of the molecular mechanisms of memory and have particular significance for type 2 diabetes (in which GluT4 activity in the periphery is impaired) and Alzheimer's disease (which is linked to impaired brain insulin signaling and for which type 2 diabetes is a key risk factor). Both diseases cause marked impairment of hippocampal memory linked to hippocampal hypometabolism, suggesting the possibility that brain GluT4 dysregulation may be one cause of cognitive impairment in these disease states.
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25
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Pacheco A, Aguayo FI, Aliaga E, Muñoz M, García-Rojo G, Olave FA, Parra-Fiedler NA, García-Pérez A, Tejos-Bravo M, Rojas PS, Parra CS, Fiedler JL. Chronic Stress Triggers Expression of Immediate Early Genes and Differentially Affects the Expression of AMPA and NMDA Subunits in Dorsal and Ventral Hippocampus of Rats. Front Mol Neurosci 2017; 10:244. [PMID: 28848384 PMCID: PMC5554379 DOI: 10.3389/fnmol.2017.00244] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Accepted: 07/20/2017] [Indexed: 12/12/2022] Open
Abstract
Previous studies in rats have demonstrated that chronic restraint stress triggers anhedonia, depressive-like behaviors, anxiety and a reduction in dendritic spine density in hippocampal neurons. In this study, we compared the effect of repeated stress on the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits in dorsal and ventral hippocampus (VH). Adult male Sprague-Dawley rats were randomly divided into control and stressed groups, and were daily restrained in their motion (2.5 h/day) during 14 days. We found that chronic stress promotes an increase in c-Fos mRNA levels in both hippocampal areas, although it was observed a reduction in the immunoreactivity at pyramidal cell layer. Furthermore, Arc mRNAs levels were increased in both dorsal and VH, accompanied by an increase in Arc immunoreactivity in dendritic hippocampal layers. Furthermore, stress triggered a reduction in PSD-95 and NR1 protein levels in whole extract of dorsal and VH. Moreover, a reduction in NR2A/NR2B ratio was observed only in dorsal pole. In synaptosomal fractions, we detected a rise in NR1 in dorsal hippocampus (DH). By indirect immunofluorescence we found that NR1 subunits rise, especially in neuropil areas of dorsal, but not VH. In relation to AMPA receptor (AMPAR) subunits, chronic stress did not trigger any change, either in dorsal or ventral hippocampal areas. These data suggest that DH is more sensitive than VH to chronic stress exposure, mainly altering the expression of NMDA receptor (NMDAR) subunits, and probably favors changes in the configuration of this receptor that may influence the function of this area.
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Affiliation(s)
- Anibal Pacheco
- Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de ChileIndependencia, Chile
| | - Felipe I Aguayo
- Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de ChileIndependencia, Chile
| | - Esteban Aliaga
- Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del MauleTalca, Chile
| | - Mauricio Muñoz
- Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de ChileIndependencia, Chile
| | - Gonzalo García-Rojo
- Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de ChileIndependencia, Chile
| | - Felipe A Olave
- Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de ChileIndependencia, Chile
| | - Nicolas A Parra-Fiedler
- Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de ChileIndependencia, Chile
| | - Alexandra García-Pérez
- Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de ChileIndependencia, Chile
| | - Macarena Tejos-Bravo
- Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de ChileIndependencia, Chile
| | - Paulina S Rojas
- Faculty of Medicine, School of Pharmacy, Universidad Andres BelloSantiago, Chile
| | - Claudio S Parra
- Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de ChileIndependencia, Chile
| | - Jenny L Fiedler
- Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de ChileIndependencia, Chile
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26
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Caruso MJ, Kamens HM, Cavigelli SA. Exposure to chronic variable social stress during adolescence alters affect-related behaviors and adrenocortical activity in adult male and female inbred mice. Dev Psychobiol 2017; 59:679-687. [PMID: 28678409 DOI: 10.1002/dev.21541] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 06/09/2017] [Indexed: 01/09/2023]
Abstract
Rodent models provide valuable insight into mechanisms that underlie vulnerability to adverse effects of early-life challenges. Few studies have evaluated sex differences in anxiogenic or depressogenic effects of adolescent social stress in a rodent model. Furthermore, adolescent stress studies often use genetically heterogeneous outbred rodents which can lead to variable results. The current study evaluated the effects of adolescent social stress in male and female inbred (BALB/cJ) mice. Adolescent mice were exposed to repeat cycles of alternating social isolation and social novelty for 4 weeks. Adolescent social stress increased anxiety-related behaviors in both sexes and depression-related behavior in females. Locomotion/exploratory behavior was also decreased in both sexes by stress. Previously stressed adult mice produced less basal fecal corticosteroids than controls. Overall, the novel protocol induced sex-specific changes in anxiety- and depression-related behaviors and corticoid production in inbred mice. The chronic variable social stress protocol used here may be beneficial to systematically investigate sex-specific neurobiological mechanisms underlying adolescent stress vulnerability where genetic background can be controlled.
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Affiliation(s)
- Michael J Caruso
- Department of Biobehavioral Health, Pennsylvania State University, University Park, Pennsylvania.,Center for Brain, Behavior, and Cognition, Pennsylvania State University, University Park, Pennsylvania
| | - Helen M Kamens
- Department of Biobehavioral Health, Pennsylvania State University, University Park, Pennsylvania.,Center for Brain, Behavior, and Cognition, Pennsylvania State University, University Park, Pennsylvania
| | - Sonia A Cavigelli
- Department of Biobehavioral Health, Pennsylvania State University, University Park, Pennsylvania.,Center for Brain, Behavior, and Cognition, Pennsylvania State University, University Park, Pennsylvania.,The Huck Institutes for the Life Sciences, Pennsylvania State University, University Park, Pennsylvania
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27
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Aoki Y, Nishimura Y, Hondrich T, Nakayama R, Igata H, Sasaki T, Ikegaya Y. Selective attenuation of electrophysiological activity of the dentate gyrus in a social defeat mouse model. J Physiol Sci 2017; 67:507-513. [PMID: 27573168 PMCID: PMC10717681 DOI: 10.1007/s12576-016-0481-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 08/20/2016] [Indexed: 01/10/2023]
Abstract
Current research on stress pathology has revealed a set of molecular and cellular mechanisms through which psychosocial stress impairs brain function. However, there are few studies that have examined how chronic stress exposure alters neuronal activity patterns at a network level. Here, we recorded ensemble neuronal activity patterns of the cortico-hippocampal network from urethane-anesthetized mice that were subjected to repeated social defeat stress. In socially defeated mice, the magnitudes of local field potential signals, including theta, slow gamma, and fast gamma oscillations, were significantly reduced in the dentate gyrus, whereas they remained unchanged in the hippocampus and somatosensory cortex. In accordance with the vast majority of histological and biochemical studies, our evidence from electrophysiological investigations highlights the dentate gyrus as a key brain area that is primarily susceptible to stress-induced dysfunction.
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Affiliation(s)
- Yuki Aoki
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yuya Nishimura
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Timm Hondrich
- Interdisciplinary Center for Neurosciences, Ruprecht-Karls-University, Im Neuenheimer Feld 504, 69120, Heidelberg, Germany
| | - Ryota Nakayama
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hideyoshi Igata
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Takuya Sasaki
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Yuji Ikegaya
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
- Center for Information and Neural Networks, 1-4 Yamadaoka, Suita, Osaka, 565-0871, Japan
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28
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Iñiguez SD, Aubry A, Riggs LM, Alipio JB, Zanca RM, Flores-Ramirez FJ, Hernandez MA, Nieto SJ, Musheyev D, Serrano PA. Social defeat stress induces depression-like behavior and alters spine morphology in the hippocampus of adolescent male C57BL/6 mice. Neurobiol Stress 2016; 5:54-64. [PMID: 27981196 PMCID: PMC5154707 DOI: 10.1016/j.ynstr.2016.07.001] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 07/16/2016] [Accepted: 07/29/2016] [Indexed: 12/18/2022] Open
Abstract
Social stress, including bullying during adolescence, is a risk factor for common psychopathologies such as depression. To investigate the neural mechanisms associated with juvenile social stress-induced mood-related endophenotypes, we examined the behavioral, morphological, and biochemical effects of the social defeat stress model of depression on hippocampal dendritic spines within the CA1 stratum radiatum. Adolescent (postnatal day 35) male C57BL/6 mice were subjected to defeat episodes for 10 consecutive days. Twenty-four h later, separate groups of mice were tested on the social interaction and tail suspension tests. Hippocampi were then dissected and Western blots were conducted to quantify protein levels for various markers important for synaptic plasticity including protein kinase M zeta (PKMζ), protein kinase C zeta (PKCζ), the dopamine-1 (D1) receptor, tyrosine hydroxylase (TH), and the dopamine transporter (DAT). Furthermore, we examined the presence of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor subunit GluA2 as well as colocalization with the post-synaptic density 95 (PSD95) protein, within different spine subtypes (filopodia, stubby, long-thin, mushroom) using an immunohistochemistry and Golgi-Cox staining technique. The results revealed that social defeat induced a depression-like behavioral profile, as inferred from decreased social interaction levels, increased immobility on the tail suspension test, and decreases in body weight. Whole hippocampal immunoblots revealed decreases in GluA2, with a concomitant increase in DAT and TH levels in the stressed group. Spine morphology analyses further showed that defeated mice displayed a significant decrease in stubby spines, and an increase in long-thin spines within the CA1 stratum radiatum. Further evaluation of GluA2/PSD95 containing-spines demonstrated a decrease of these markers within long-thin and mushroom spine types. Together, these results indicate that juvenile social stress induces GluA2- and dopamine-associated dysregulation in the hippocampus - a neurobiological mechanism potentially underlying the development of mood-related syndromes as a consequence of adolescent bullying.
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Affiliation(s)
- Sergio D. Iñiguez
- Department of Psychology, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79902, USA
- Department of Psychology, California State University, San Bernardino, CA, 92407, USA
| | - Antonio Aubry
- Department of Psychology, Hunter College, New York, NY, 10065, USA
- The Graduate Center of CUNY, New York, NY, USA
| | - Lace M. Riggs
- Department of Psychology, California State University, San Bernardino, CA, 92407, USA
| | - Jason B. Alipio
- Department of Psychology, California State University, San Bernardino, CA, 92407, USA
| | | | - Francisco J. Flores-Ramirez
- Department of Psychology, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79902, USA
| | - Mirella A. Hernandez
- Department of Psychology, The University of Texas at El Paso, 500 W. University Ave., El Paso, TX, 79902, USA
- Department of Psychology, California State University, San Bernardino, CA, 92407, USA
| | - Steven J. Nieto
- Department of Psychology, California State University, San Bernardino, CA, 92407, USA
| | - David Musheyev
- Department of Psychology, Hunter College, New York, NY, 10065, USA
| | - Peter A. Serrano
- Department of Psychology, Hunter College, New York, NY, 10065, USA
- The Graduate Center of CUNY, New York, NY, USA
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29
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EphB2 in the Medial Prefrontal Cortex Regulates Vulnerability to Stress. Neuropsychopharmacology 2016; 41:2541-56. [PMID: 27103064 PMCID: PMC4987853 DOI: 10.1038/npp.2016.58] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 03/28/2016] [Accepted: 04/12/2016] [Indexed: 01/23/2023]
Abstract
The ephrin B2 (EphB2) receptor is a tyrosine kinase receptor that is associated with synaptic development and maturation. It has recently been implicated in cognitive deficits and anxiety. However, still unknown is the involvement of EphB2 in the vulnerability to stress. In the present study, we observed decreases in EphB2 levels and their downstream molecules in the medial prefrontal cortex (mPFC) but not in the orbitofrontal cortex (OFC) in mice that were susceptible to chronic social defeat stress. The activation of EphB2 receptors with EphrinB1-Fc in the mPFC produced stress-resistant and antidepressant-like behavioral effects in susceptible mice that lasted for at least 10 days. EphB2 receptor knockdown by short-hairpin RNA in the mPFC increased the susceptibility to stress and induced depressive-like behaviors in a subthreshold chronic social defeat stress paradigm. These behavioral effects were associated with changes in the phosphorylation of cofilin and membrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking and the expression of some synaptic proteins in the mPFC. We also found that EphB2 regulated stress-induced spine remodeling in the mPFC. Altogether, these results indicate that EphB2 is a critical regulator of stress vulnerability and might be a potential target for the treatment of depression.
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30
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Antidepressant-Like and Anxiolytic-Like Effects of ZBD-2, a Novel Ligand for the Translocator Protein (18 kDa). Neuromolecular Med 2016; 19:57-68. [PMID: 27544207 DOI: 10.1007/s12017-016-8425-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 07/02/2016] [Indexed: 12/17/2022]
Abstract
Activation of translocator protein (18 kDa) (TSPO) plays an important role to mediate rapid anxiolytic efficacy in stress response and stress-related disorders by the production of neurosteroids. However, little is known about the ligand of TSPO on the anxiety-like and depressive behaviors and the underlying mechanisms in chronic unpredictable mild stress (UCMS) mice. In the present study, a novel ligand of TSPO, ZBD-2 [N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide] synthesized by our laboratory, was used to evaluate the anxiolytic and antidepressant efficacy and to elucidate the underlying mechanisms. ZBD-2 (3 mg/kg) significantly attenuated anxiety-like and depressive behaviors in the UCMS mice, which was blocked by TSPO antagonist PK11195 (3 mg/kg). Treatment of ZBD-2 reversed the decrease in biogenic amines (norepinephrine, dopamine, and serotonin) in the brain region of hippocampus in the UCMS mice. The decreases in TSPO, GluN2B-containing N-methyl-D-aspartate (NMDA) receptors, GluA1, p-GluA1-Ser831, p-GluA1-Ser845, PSD-95, and GABAA-a2 were integrated with the increases of CaMKII and iNOS levels in the hippocampus of the UCMS mice. ZBD-2 significantly reversed the changes of above proteins. However, ZBD-2 or PK11195 treatment did not affect the levels of GluN2A-containing NMDA receptors and the total levels of GAD67. Our study provides strong evidences that ZBD-2 has a therapeutic effect on chronic stress-related disorders such as depression and anxiety through regulating the biogenic amine levels and the synaptic proteins in the hippocampus.
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31
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Kimmel M, Kaminsky Z, Payne JL. Biomarker or pathophysiology? The role of DNA methylation in postpartum depression. Epigenomics 2016; 5:473-5. [PMID: 24059792 DOI: 10.2217/epi.13.51] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Mary Kimmel
- Johns Hopkins School of Medicine, Department of Psychiatry, 550 N Broadway, Suite 305, Baltimore, MD 21205, USA
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32
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Santarelli S, Wagner KV, Labermaier C, Uribe A, Dournes C, Balsevich G, Hartmann J, Masana M, Holsboer F, Chen A, Müller MB, Schmidt MV. SLC6A15, a novel stress vulnerability candidate, modulates anxiety and depressive-like behavior: involvement of the glutamatergic system. Stress 2016; 19:83-90. [PMID: 26585320 DOI: 10.3109/10253890.2015.1105211] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Major depression is a multifactorial disease, involving both environmental and genetic risk factors. Recently, SLC6A15 - a neutral amino acid transporter mainly expressed in neurons - was proposed as a new candidate gene for major depression and stress vulnerability. Risk allele carriers for a single nucleotide polymorphism (SNP) in a SLC6A15 regulatory region display altered hippocampal volume, glutamate levels, and hypothalamus-pituitary-adrenal axis activity, all markers associated with major depression. Despite this genetic link between SLC6A15 and depression, its functional role with regard to the development and maintenance of depressive disorder is still unclear. The aim of the current study was therefore to characterize the role of mouse slc6a15 in modulating brain function and behavior, especially in relation to stress as a key risk factor for the development of mood disorders. We investigated the effects of slc6a15 manipulation using two mouse models, a conventional slc6a15 knock-out mouse line (SLC-KO) and a virus-mediated hippocampal slc6a15 overexpression (SLC-OE) model. Mice were tested under basal conditions and following chronic social stress. We found that SLC-KO animals displayed a similar behavioral profile to wild-type littermates (SLC-WT) under basal conditions. Interestingly, following chronic social stress SLC-KO animals showed lower levels of anxiety- and depressive-like behavior compared to stressed WT littermates. In support of these findings, SLC-OE animals displayed increased anxiety-like behavior already under basal condition. We also provide evidence that GluR1 expression in the dentate gyrus, but not GluR2 or NR1, are regulated by slc6a15 expression, and may contribute to the difference in stress responsiveness observed between SLC-KO and SLC-WT animals. Taken together, our data demonstrate that slc6a15 plays a role in modulating emotional behavior, possibly mediated by its impact on glutamatergic neurotransmission.
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MESH Headings
- Alleles
- Amino Acid Transport Systems, Neutral/genetics
- Animals
- Anxiety/genetics
- Behavior, Animal
- Corticosterone/blood
- Dentate Gyrus/metabolism
- Depression/genetics
- Disease Models, Animal
- Gene Expression Regulation
- Gene Knock-In Techniques
- Genotype
- Hippocampus/metabolism
- Male
- Mice
- Mice, Knockout
- Mood Disorders/genetics
- Nerve Tissue Proteins/genetics
- Polymorphism, Single Nucleotide
- RNA, Messenger/metabolism
- Receptors, AMPA/genetics
- Receptors, N-Methyl-D-Aspartate/genetics
- Risk Factors
- Stress, Psychological/genetics
- Stress, Psychological/metabolism
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Affiliation(s)
- S Santarelli
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - K V Wagner
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - C Labermaier
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - A Uribe
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - C Dournes
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - G Balsevich
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - J Hartmann
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - M Masana
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - F Holsboer
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - A Chen
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - M B Müller
- a Max Planck Institute of Psychiatry , Munich , Germany
| | - M V Schmidt
- a Max Planck Institute of Psychiatry , Munich , Germany
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33
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Kvarta MD, Bradbrook KE, Dantrassy HM, Bailey AM, Thompson SM. Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses. J Neurophysiol 2015; 114:1713-24. [PMID: 26180121 DOI: 10.1152/jn.00359.2015] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 07/13/2015] [Indexed: 12/16/2022] Open
Abstract
Chronic stress is thought to impart risk for depression via alterations in brain structure and function, but contributions of specific mediators in generating these changes remain unclear. We test the hypothesis that stress-induced increases in corticosterone (CORT), the primary rodent glucocorticoid, are the key mediator of stress-induced depressive-like behavioral changes and synaptic dysfunction in the rat hippocampus. In rats, we correlated changes in cognitive and affective behavioral tasks (spatial memory consolidation, anhedonia, and neohypophagia) with impaired excitatory strength at temporoammonic-CA1 (TA-CA1) synapses, an archetypical stress-sensitive excitatory synapse. We tested whether elevated CORT was sufficient and necessary to generate a depressive-like behavioral phenotype and decreased excitatory signaling observed at TA-CA1 after chronic unpredictable stress (CUS). Chronic CORT administration induced an anhedonia-like behavioral state and neohypophagic behavior. Like CUS, chronic, but not acute, CORT generated an impaired synaptic phenotype characterized by reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptor-mediated excitation at TA-CA1 synapses, decreased AMPA-type glutamate receptor subunit 1 protein expression, and altered serotonin-1B receptor-mediated potentiation. Repeatedly blunting stress-induced increases of CORT during CUS with the CORT synthesis inhibitor metyrapone (MET) prevented these stress-induced neurobehavioral changes. MET also prevented the CUS-induced impairment of spatial memory consolidation. We conclude that corticosterone is sufficient and necessary to mediate glutamatergic dysfunction underlying stress-induced synaptic and behavioral phenotypes. Our results indicate that chronic excessive glucocorticoids cause specific synaptic deficits in the hippocampus, a major center for cognitive and emotional processing, that accompany stress-induced behavioral dysfunction. Maintaining excitatory strength at stress-sensitive synapses at key loci throughout corticomesolimbic reward circuitry appears critical for maintaining normal cognitive and emotional behavior.
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Affiliation(s)
- Mark D Kvarta
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, Baltimore, Maryland; Medical Scientist Training Program, University of Maryland School of Medicine, Baltimore, Maryland; and
| | - Keighly E Bradbrook
- Department of Psychology, Saint Mary's College of Maryland, St. Mary's City, Maryland
| | - Hannah M Dantrassy
- Department of Psychology, Saint Mary's College of Maryland, St. Mary's City, Maryland
| | - Aileen M Bailey
- Department of Psychology, Saint Mary's College of Maryland, St. Mary's City, Maryland
| | - Scott M Thompson
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, Baltimore, Maryland;
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34
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Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X. An excitatory synapse hypothesis of depression. Trends Neurosci 2015; 38:279-94. [PMID: 25887240 DOI: 10.1016/j.tins.2015.03.003] [Citation(s) in RCA: 214] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 02/23/2015] [Accepted: 03/17/2015] [Indexed: 12/14/2022]
Abstract
Depression is a common cause of mortality and morbidity, but the biological bases of the deficits in emotional and cognitive processing remain incompletely understood. Current antidepressant therapies are effective in only some patients and act slowly. Here, we propose an excitatory synapse hypothesis of depression in which chronic stress and genetic susceptibility cause changes in the strength of subsets of glutamatergic synapses at multiple locations, including the prefrontal cortex (PFC), hippocampus, and nucleus accumbens (NAc), leading to a dysfunction of corticomesolimbic reward circuitry that underlies many of the symptoms of depression. This hypothesis accounts for current depression treatments and suggests an updated framework for the development of better therapeutic compounds.
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Affiliation(s)
- Scott M Thompson
- Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Department of Psychiatry, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.
| | - Angy J Kallarackal
- Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA
| | - Mark D Kvarta
- Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Medical Scientist Training Program, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA
| | - Adam M Van Dyke
- Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA
| | - Tara A LeGates
- Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA
| | - Xiang Cai
- Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Department of Physiology, Southern Illinois University, Carbondale, IL 62901, USA
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35
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Wagner KV, Hartmann J, Labermaier C, Häusl AS, Zhao G, Harbich D, Schmid B, Wang XD, Santarelli S, Kohl C, Gassen NC, Matosin N, Schieven M, Webhofer C, Turck CW, Lindemann L, Jaschke G, Wettstein JG, Rein T, Müller MB, Schmidt MV. Homer1/mGluR5 activity moderates vulnerability to chronic social stress. Neuropsychopharmacology 2015; 40:1222-33. [PMID: 25409593 PMCID: PMC4367467 DOI: 10.1038/npp.2014.308] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 11/03/2014] [Accepted: 11/04/2014] [Indexed: 12/28/2022]
Abstract
Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. Yet, the specific role of Homer1 in this context remains poorly understood. We used chronic social defeat stress as an established animal model of depression and investigated changes in transcription of Homer1a and Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we investigated the consequences of Homer1 deletion, overexpression of Homer1a, and chronic administration of the mGluR5 inverse agonist CTEP (2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine) on the effects of chronic stress. In mice exposed to chronic stress, Homer1b/c, but not Homer1a, mRNA was upregulated and, accordingly, Homer1/mGluR5 coupling was disrupted. We found a marked hyperactivity behavior as well as a dysregulated hypothalamic-pituitary-adrenal axis activity in chronically stressed Homer1 knockout (KO) mice. Chronic administration of the selective and orally bioavailable mGluR5 inverse agonist, CTEP, was able to recover behavioral alterations induced by chronic stress, whereas overexpression of Homer1a in the hippocampus led to an increased vulnerability to chronic stress, reflected in an increased physiological response to stress as well as enhanced depression-like behavior. Overall, our results implicate the glutamatergic system in the emergence of stress-induced psychiatric disorders, and support the Homer1/mGluR5 complex as a target for the development of novel antidepressant agents.
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Affiliation(s)
- Klaus V Wagner
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Jakob Hartmann
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Christiana Labermaier
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Alexander S Häusl
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Gengjing Zhao
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Daniela Harbich
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Bianca Schmid
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Xiao-Dong Wang
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Sara Santarelli
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Christine Kohl
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Nils C Gassen
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Natalie Matosin
- Faculty of Science, Medicine and Health and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia,Schizophrenia Research Institute, Sydney NSW, Australia
| | - Marcel Schieven
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Christian Webhofer
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Christoph W Turck
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Lothar Lindemann
- Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology, and Rare Diseases Translational Area (NORD), Basel, Switzerland
| | - Georg Jaschke
- Roche Pharmaceutical Research and Early Development, Discovery Chemistry, Basel, Switzerland
| | - Joseph G Wettstein
- Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology, and Rare Diseases Translational Area (NORD), Basel, Switzerland
| | - Theo Rein
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Marianne B Müller
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
| | - Mathias V Schmidt
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany,Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany, Tel: +49 89 30622 519, Fax: +49 89 30622 610, E-mail:
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36
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Tomizawa H, Matsuzawa D, Ishii D, Matsuda S, Kawai K, Mashimo Y, Sutoh C, Shimizu E. Methyl-donor deficiency in adolescence affects memory and epigenetic status in the mouse hippocampus. GENES BRAIN AND BEHAVIOR 2015; 14:301-9. [DOI: 10.1111/gbb.12207] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 01/29/2015] [Accepted: 02/06/2015] [Indexed: 12/21/2022]
Affiliation(s)
- H. Tomizawa
- Department of Cognitive Behavioral Physiology
| | - D. Matsuzawa
- Department of Cognitive Behavioral Physiology
- Research Center for Child Mental Development, Graduate School of Medicine; Chiba University; Chiba
| | - D. Ishii
- Department of Cognitive Behavioral Physiology
| | - S. Matsuda
- Department of Cognitive Behavioral Physiology
- Department of Ultrastructural Research, National Institute of Neuroscience; National Center of Neurology and Psychiatry; Kodaira
| | - K. Kawai
- Department of Cognitive Behavioral Physiology
| | - Y. Mashimo
- Department of Public Health, Graduate School of Medicine; Chiba University; Chiba Japan
| | - C. Sutoh
- Department of Cognitive Behavioral Physiology
- Research Center for Child Mental Development, Graduate School of Medicine; Chiba University; Chiba
| | - E. Shimizu
- Department of Cognitive Behavioral Physiology
- Research Center for Child Mental Development, Graduate School of Medicine; Chiba University; Chiba
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Beery AK, Kaufer D. Stress, social behavior, and resilience: insights from rodents. Neurobiol Stress 2015; 1:116-127. [PMID: 25562050 PMCID: PMC4281833 DOI: 10.1016/j.ynstr.2014.10.004] [Citation(s) in RCA: 239] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Accepted: 10/24/2014] [Indexed: 11/20/2022] Open
Abstract
The neurobiology of stress and the neurobiology of social behavior are deeply intertwined. The social environment interacts with stress on almost every front: social interactions can be potent stressors; they can buffer the response to an external stressor; and social behavior often changes in response to stressful life experience. This review explores mechanistic and behavioral links between stress, anxiety, resilience, and social behavior in rodents, with particular attention to different social contexts. We consider variation between several different rodent species and make connections to research on humans and non-human primates.
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Affiliation(s)
- Annaliese K. Beery
- Department of Psychology, Department of Biology, Neuroscience Program, Smith College, Northampton, MA, USA
| | - Daniela Kaufer
- Department of Integrative Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA
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38
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Mairesse J, Van Camp G, Gatta E, Marrocco J, Reynaert ML, Consolazione M, Morley-Fletcher S, Nicoletti F, Maccari S. Sleep in prenatally restraint stressed rats, a model of mixed anxiety-depressive disorder. ADVANCES IN NEUROBIOLOGY 2015; 10:27-44. [PMID: 25287534 DOI: 10.1007/978-1-4939-1372-5_2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Prenatal restraint stress (PRS) can induce persisting changes in individual's development. PRS increases anxiety and depression-like behaviors and induces changes in the hypothalamo-pituitary-adrenal (HPA) axis in adult PRS rats after exposure to stress. Since adaptive capabilities also depend on temporal organization and synchronization with the external environment, we studied the effects of PRS on circadian rhythms, including the sleep-wake cycle, that are parameters altered in depression. Using a restraint stress during gestation, we showed that PRS induced phase advances in hormonal/behavioral circadian rhythms in adult rats, and an increase in the amount of paradoxical sleep, positively correlated to plasma corticosterone levels. Plasma corticosterone levels were also correlated with immobility in the forced swimming test, indicating a depressive-like profile in the PRS rats. We observed comorbidity with anxiety-like profile on PRS rats that was correlated with a reduced release of glutamate in the ventral hippocampus. Pharmacological approaches aimed at modulating glutamate release may represent a novel therapeutic strategy to treat stress-related disorders. Finally, since depressed patients exhibit changes in HPA axis activity and in circadian rhythmicity as well as in the paradoxical sleep regulation, we suggest that PRS could represent an original animal model of depression.
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Affiliation(s)
- Jérôme Mairesse
- International Associated Laboratory-Prenatal Stress and Neurodegenerative Diseases, Neural Plasticity Team-UMR CNRS/USTL n 8576 Structural and Functional Glycobiology Unit, University of Lille 1, Lille, France
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39
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Sekio M, Seki K. Lipopolysaccharide-induced depressive-like behavior is associated with α₁-adrenoceptor dependent downregulation of the membrane GluR1 subunit in the mouse medial prefrontal cortex and ventral tegmental area. Int J Neuropsychopharmacol 2014; 18:pyu005. [PMID: 25539502 PMCID: PMC4368860 DOI: 10.1093/ijnp/pyu005] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Chronic stress-induced depressive-like behavior is relevant to inflammatory immune activation. However, the neurobiological alterations in the brain following the central inflammatory immune activation remain elusive. METHODS Therefore, we investigated the neurobiological alterations during depressive-like behavior induced in mice by systemic administration of lipopolysaccharide (LPS; 1.2 mg/kg administered twice at a 30-min interval via intraperitoneal injection). RESULTS At 24 h after the second administration of LPS, an increased immobility time in the tail suspension test and the forced swimming test were observed, as well as reduced sucrose preference. Protein levels of the AMPA receptor GluR1 were significantly decreased at the plasma membrane in the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA), while levels of the GluR2 were increased at the plasma membrane in the nucleus accumbens (NAc) at 24h after LPS. However, total GluR1 and GluR2 protein levels in the mPFC, VTA, and NAc were not affected by LPS. Moreover, LPS facilitated release of noradrenaline in the mPFC and VTA, but not in the NAc. Consistently, systemic administration of prazosin, an α1-adrenoceptor antagonist, blocked the LPS-induced downregulation of the membrane GluR1 subunit in both the mPFC and VTA and also blocked the upregulation of the membrane GluR2 subunit in the NAc. Intracerebroventricular administration of prazosin 30 min before LPS injection abrogated the LPS-induced depressive-like behaviors. In opposition, administration of propranolol, a β-adrenoceptor antagonist, did not affect the LPS-induced downregulation of GluR1, the upregulation of GluR2, or the depressive-like behavior. CONCLUSIONS These results suggest that LPS-activated α1-adrenoceptor-induced downregulation of membrane GluR1 in the mPFC and VTA is associated with inflammation-induced depressive-like behavior.
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Affiliation(s)
| | - Kenjiro Seki
- Department of Pharmacology, School of Pharmaceutical Science, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima 963-8611, Japan.
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40
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Jakob S, Schraut KG, Schmitt AG, Scholz CJ, Ortega G, Steinbusch HW, Lesch KP, van den Hove DLA. Differential effects of prenatal stress in female 5-HTT-deficient mice: towards molecular mechanisms of resilience. Dev Neurosci 2014; 36:454-64. [PMID: 25195605 DOI: 10.1159/000363695] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 05/13/2014] [Indexed: 11/19/2022] Open
Abstract
Prenatal stress (PS) exposure is known to increase the risk of developing emotional disorders like major depression in later life. However, some individuals do not succumb to adversity following developmental stress exposure, a phenomenon referred to as resilience. To date, the molecular mechanisms explaining why some subjects are vulnerable and others more resilient to PS are far from understood. Recently, we have shown that the serotonin transporter (5-HTT) gene may play a modulating role in rendering individuals susceptible or resilient to PS. However, it is not clear which molecular players are mediating the interaction between PS and the 5-Htt genotype in the context of vulnerability and resilience to PS. For this purpose, we performed a microarray study with the help of Affymetrix GeneChip® Mouse Genome 430 2.0 Array, in which we separated wild-type and heterozygous 5-Htt-deficient (5-Htt+/-) PS offspring into susceptible and resilient offspring according to their performance in the forced swim test. Performance-oriented LIMMA analysis on the mRNA expression microarray data was followed by subsequent Spearman's correlation analysis linking the individual qRT-PCR mRNA expression data to various anxiety- and depression-related behavioral and neuroendocrine measures. Results indicate that, amongst others, Fos-induced growth factor (Figf), galanin receptor 3 (Galr3), growth hormone (Gh) and prolactin (Prl) were differentially expressed specifically in resilient offspring when compared to controls, and that the hippocampal expression of these genes showed several strong correlations with various measures of the hypothalamus-pituitary-adrenal axis (re)activity. In conclusion, there seems to be an intricate interplay between the expression of Figf, Galr3, Gh and Prl and neuroendocrine regulation, which may be critical in mediating resilience to PS exposure. More insight into the exact role of these molecular players may significantly enhance the development of new treatment strategies for stress-related emotional disorders.
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Affiliation(s)
- Sissi Jakob
- Department of Neuroscience, School for Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, The Netherlands
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41
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Tomar A, Polygalov D, Chattarji S, McHugh TJ. The dynamic impact of repeated stress on the hippocampal spatial map. Hippocampus 2014; 25:38-50. [PMID: 25139366 DOI: 10.1002/hipo.22348] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 08/11/2014] [Indexed: 01/26/2023]
Abstract
Stress alters the function of many physiological processes throughout the body, including in the brain. A neural circuit particularly vulnerable to the effects of stress is the hippocampus, a key component of the episodic and spatial memory system in both humans and rodents. Earlier studies have provided snapshots of morphological, molecular, physiological and behavioral changes in the hippocampus following either acute or repeated stress. However, the cumulative impact of repeated stress on in vivo hippocampal physiology remains unexplored. Here we report the stress-induced modulation of the spatially receptive fields of the hippocampal CA1 'place cells' as mice explore familiar and novel tracks after 5 and 10 days of immobilization stress. We find that similar to what has been observed following acute stress, five days of repeated stress results in decreased excitability of CA1 pyramidal cells. Following ten days of chronic stress, however, this decreased hippocampal excitability is no longer evident, suggesting adaptation may have occurred. In addition to these changes in neuronal excitability, we find deficient context discrimination, wherein both short-term and chronic stress impair the ability of the hippocampus to unambiguously distinguish novel and familiar environments. These results suggest that a loss of network flexibility may underlie some of the behavioral deficits accompanying chronic stress.
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Affiliation(s)
- Anupratap Tomar
- National Centre for Biological Sciences, Bangalore, India; Manipal University, Manipal, India
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42
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Distinct effects of repeated restraint stress on basolateral amygdala neuronal membrane properties in resilient adolescent and adult rats. Neuropsychopharmacology 2014; 39:2114-30. [PMID: 24619244 PMCID: PMC4104329 DOI: 10.1038/npp.2014.60] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 02/24/2014] [Accepted: 02/27/2014] [Indexed: 12/30/2022]
Abstract
Severe and repeated stress has damaging effects on health, including initiation of depression and anxiety. Stress that occurs during development has long-lasting and particularly damaging effects on emotion. The basolateral amygdala (BLA) plays a key role in many affective behaviors, and repeated stress causes different forms of BLA hyperactivity in adolescent and adult rats. However, the mechanism is not known. Furthermore, not every individual is susceptible to the negative consequences of stress. Differences in the effects of stress on the BLA might contribute to determine whether an individual will be vulnerable or resilient to the effects of stress on emotion. The purpose of this study is to test the cellular underpinnings for age dependency of BLA hyperactivity after stress, and whether protective changes occur in resilient individuals. To test this, the effects of repeated stress on membrane excitability and other membrane properties of BLA principal neurons were compared between adult and adolescent rats, and between vulnerable and resilient rats, using in vitro whole-cell recordings. Vulnerability was defined by adrenal gland weight, and verified by body weight gain after repeated restraint stress, and fecal pellet production during repeated restraint sessions. We found that repeated stress increased the excitability of BLA neurons, but in a manner that depended on age and BLA subnucleus. Furthermore, stress resilience was associated with an opposite pattern of change, with increased slow afterhyperpolarization (AHP) potential, whereas vulnerability was associated with decreased medium AHP. The opposite outcomes in these two populations were further distinguished by differences of anxiety-like behavior in the elevated plus maze that were correlated with BLA neuronal excitability and AHP. These results demonstrate a substrate for BLA hyperactivity after repeated stress, with distinct membrane properties to target, as well as age-dependent factors that contribute to resilience to the effects of stress.
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43
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Labermaier C, Kohl C, Hartmann J, Devigny C, Altmann A, Weber P, Arloth J, Quast C, Wagner KV, Scharf SH, Czibere L, Widner-Andrä R, Brenndörfer J, Landgraf R, Hausch F, Jones KA, Müller MB, Uhr M, Holsboer F, Binder EB, Schmidt MV. A polymorphism in the Crhr1 gene determines stress vulnerability in male mice. Endocrinology 2014; 155:2500-10. [PMID: 24773341 DOI: 10.1210/en.2013-1986] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Chronic stress is a risk factor for psychiatric disorders but does not necessarily lead to uniform long-term effects on mental health, suggesting modulating factors such as genetic predispositions. Here we address the question whether natural genetic variations in the mouse CRH receptor 1 (Crhr1) locus modulate the effects of adolescent chronic social stress (ACSS) on long-term stress hormone dysregulation in outbred CD1 mice, which allows a better understanding of the currently reported genes × environment interactions of early trauma and CRHR1 in humans. We identified 2 main haplotype variants in the mouse Crhr1 locus that modulate the long-term effects of ACSS on basal hypothalamic-pituitary-adrenal axis activity. This effect is likely mediated by higher levels of CRHR1, because Crhr1 mRNA expression and CRHR1 binding were enhanced in risk haplotype carriers. Furthermore, a CRHR1 receptor antagonist normalized these long-term effects. Deep sequencing of the Crhr1 locus in CD1 mice revealed a large number of linked single-nucleotide polymorphisms with some located in important regulatory regions, similar to the location of human CRHR1 variants implicated in modulating gene × stress exposure interactions. Our data support that the described gene × stress exposure interaction in this animal model is based on naturally occurring genetic variations in the Crhr1 gene associated with enhanced CRHR1-mediated signaling. Our results suggest that patients with a specific genetic predisposition in the CRHR1 gene together with an exposure to chronic stress may benefit from a treatment selectively antagonizing CRHR1 hyperactivity.
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Affiliation(s)
- Christiana Labermaier
- Max Planck Institute of Psychiatry (C.L., C.K., J.H., C.D., A.A, P.W., J.A., C.Q., K.V.W., S.H.S., L.C., R.W-A., J.B., R.L., F.H., M.U., F.H., E.B.B., M.V.S.), 80804 Munich, Germany; Lundbeck Research USA (K.A.J.), Paramus, New Jersey 07652; and Johannes Gutenberg University Medical Center (M.B.M.), 55131 Mainz, Germany
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44
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Alò R, Avolio E, Mele M, Storino F, Canonaco A, Carelli A, Canonaco M. Excitatory/inhibitory equilibrium of the central amygdala nucleus gates anti-depressive and anxiolytic states in the hamster. Pharmacol Biochem Behav 2014; 118:79-86. [DOI: 10.1016/j.pbb.2014.01.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 12/19/2013] [Accepted: 01/17/2014] [Indexed: 12/12/2022]
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45
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Uzunova G, Hollander E, Shepherd J. The role of ionotropic glutamate receptors in childhood neurodevelopmental disorders: autism spectrum disorders and fragile x syndrome. Curr Neuropharmacol 2014; 12:71-98. [PMID: 24533017 PMCID: PMC3915351 DOI: 10.2174/1570159x113116660046] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 08/20/2013] [Accepted: 09/25/2013] [Indexed: 12/20/2022] Open
Abstract
Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS.
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Affiliation(s)
- Genoveva Uzunova
- Autism and Obsessive Compulsive Spectrum Program, Department of Psychiatry, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th St, Bronx, New York 10467-2490
| | - Eric Hollander
- Autism and Obsessive Compulsive Spectrum Program, Department of Psychiatry, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th St, Bronx, New York 10467-2490
| | - Jason Shepherd
- Department of Neurobiology and Anatomy, University of Utah School of Medicine, 531A Wintrobe, 20N 1900 E, Salt Lake City, Utah 84132
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46
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Kaminsky Z, Payne J. Seeing the future: epigenetic biomarkers of postpartum depression. Neuropsychopharmacology 2014; 39:233-4. [PMID: 24317310 PMCID: PMC3857665 DOI: 10.1038/npp.2013.238] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Zachary Kaminsky
- The Mood Disorders Center, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jennifer Payne
- The Mood Disorders Center, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA,E-mail:
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47
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Sexually dimorphic long-term effects of an early life experience on AMPA receptor subunit expression in rat brain. Neuroscience 2014; 257:49-64. [DOI: 10.1016/j.neuroscience.2013.10.073] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 10/04/2013] [Accepted: 10/23/2013] [Indexed: 12/26/2022]
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48
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Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci 2013; 33:15669-74. [PMID: 24089474 DOI: 10.1523/jneurosci.2588-13.2013] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Chronic stress promotes depression, but how it disrupts cognition and mood remains unknown. Chronic stress causes atrophy of pyramidal cell dendrites in the hippocampus and cortex in human and animal models, and a depressive-like behavioral state. We now test the hypothesis that excitatory temporoammonic (TA) synapses in the distal dendrites of CA1 pyramidal cells in rats are altered by chronic unpredictable stress (CUS) and restored by chronic antidepressant treatment, in conjunction with the behavioral consequences of CUS. We observed a decrease in AMPAR-mediated excitation at TA-CA1 synapses, but not Schaffer collateral-CA1 synapses, after CUS, with a corresponding layer-specific decrease in GluA1 expression. Both changes were reversed by chronic fluoxetine. CUS also disrupted long-term memory consolidation in the Morris water maze, a function of TA-CA1 synapses. The decreases in TA-CA1 AMPAR-mediated excitation and performance in the consolidation test were correlated positively with decreases in sucrose preference, a measure of anhedonia. We conclude that chronic stress selectively decreases AMPAR number and function at specific synapses and suggest that this underlies various depressive endophenotypes. Our findings provide evidence that glutamatergic dysfunction is an underlying cause of depression and that current first-line antidepressant drugs act by restoring excitatory synaptic strength. Our findings suggest novel therapeutic targets for this debilitating disease.
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49
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A combined α7 nicotinic acetylcholine receptor agonist and monoamine reuptake inhibitor, NS9775, represents a novel profile with potential benefits in emotional and cognitive disturbances. Neuropharmacology 2013; 73:183-91. [DOI: 10.1016/j.neuropharm.2013.04.060] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 04/25/2013] [Accepted: 04/28/2013] [Indexed: 12/23/2022]
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50
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Basal variability in CREB phosphorylation predicts trait-like differences in amygdala-dependent memory. Proc Natl Acad Sci U S A 2013; 110:16645-50. [PMID: 24062441 DOI: 10.1073/pnas.1304665110] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Much of what is known about the neurobiology of learning and memory comes from studies of the average behavior. In contrast, intersubject differences that emerge within groups are difficult to study systematically and are often excluded from scientific discussion. Nevertheless, population-wide variability is a virtually universal feature of both complex traits, such as intelligence, and hardwired responses, such as defensive behaviors. Here, we use outbred rats to investigate if cAMP response element-binding protein (CREB), a transcription factor that has long been known in experimental settings to be crucial for associative plasticity, participates in natural memory phenotypes. Using a combination of behavioral, biochemical, and viral techniques, we show that a subset of rats with trait-like deficits in aversive memory have basally reduced CREB activity in the lateral amygdala but can be induced to perform at average levels by directly or indirectly enhancing pretraining CREB phosphorylation. These data suggest that endogenous CREB activity in the amygdala may set a critical threshold for plasticity during memory formation.
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