The DOI matches its Crossref record; 329 of the 329 references it cites were found in a registry or an index.
GABAergic Control of Depression-Related Brain States
Open accessAbstract
The GABAergic deficit hypothesis of major depressive disorders (MDDs) posits that reduced γ-aminobutyric acid (GABA) concentration in brain, impaired function of GABAergic interneurons, altered expression and function of GABA(A) receptors, and changes in GABAergic transmission dictated by altered chloride homeostasis can contribute to the etiology of MDD. Conversely, the hypothesis posits that the efficacy of currently used antidepressants is determined by their ability to enhance GABAergic neurotransmission. We here provide an update for corresponding evidence from studies of patients and preclinical animal models of depression. In addition, we propose an explanation for the continued lack of genetic evidence that explains the considerable heritability of MDD. Lastly, we discuss how alterations in GABAergic transmission are integral to other hypotheses of MDD that emphasize (i) the role of monoaminergic deficits, (ii) stress-based etiologies, (iii) neurotrophic deficits, and (iv) the neurotoxic and neural circuit-impairing consequences of chronic excesses of glutamate. We propose that altered GABAergic transmission serves as a common denominator of MDD that can account for all these other hypotheses and that plays a causal and common role in diverse mechanistic etiologies of depressive brain states and in the mechanism of action of current antidepressant drug therapies.
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“These findings reveal alterations at the levels of intracellular signaling, gene expression, neurotrophic factors, neurogenesis, neuroinflammation, excitatory and inhibitory neurotransmission, and synaptic number and function, and have been described in several brain regions implicated in depression 13-22 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [14]
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Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
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Duman, R. S., Sanacora, G., & Krystal, J. H. (2019) · Neuron · doi:10.1016/j.neuron.2019.03.013 · Cited by 1,026
Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model
Price, R. B., & Duman, R. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0615-x · Cited by 739
Ferguson, B. R., & Gao, W.-J. (2018) · Frontiers in Neural Circuits · doi:10.3389/fncir.2018.00037 · Cited by 594
Influence of glutamate and GABA transport on brain excitatory/inhibitory balance
Sears, S. M. S., & Hewett, S. J. (2021) · Experimental Biology and Medicine · doi:10.1177/1535370221989263 · Cited by 371
Fee, C., Banasr, M., & Sibille, E. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.05.024 · Cited by 329
Metadata
- Authors
- Luscher, B., & Fuchs, T.
- Affiliations
- Pennsylvania State University (US)
- ORCID
- Fuchs, Thomas
- Venue
- Advances in Pharmacology
- Publisher
- Elsevier
- Published
- 2015
- Volume
- 73
- Pages
- 97-144
- ISSN
- 1054-3589 (ISSN-L)
- PMC
- PMC4784429
- OpenAlex
- W135939678
- Cited by
- 149
- References
- 329
- Citations by year
- 2026: 15 · 2025: 12 · 2024: 16 · 2023: 10 · 2022: 9 · 2021: 23 · 2020: 23 · 2019: 18 · 2018: 8 · 2017: 6 · 2016: 8 · 2015: 1
- FWCI
- 22.97
- Type
- book chapter
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Advances in pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Universität Zürich
- National Institute of Mental Health (R21MH097247, R01MH099851, R01MH083911, MH099851, MH097247, MH083911, RC1MH089111)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- major depressive disorder, GABAergic neurotransmission, GABAA receptor, GABAergic interneurons, chloride homeostasis, antidepressant mechanism, glutamate excitotoxicity, neural circuits, animal models of depression
- MeSH terms
- Animals, Antidepressive Agents, Brain, Major Depressive Disorder, Disease Models, Animal, gamma-Aminobutyric Acid, Humans, Synaptic Transmission, Receptors, GABA-A
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