Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment
Open accessAbstract
BACKGROUND: Major depressive disorder is increasingly recognized to involve functional deficits in both gamma-aminobutyric acid (GABA)ergic and glutamatergic synaptic transmission. To elucidate the relationship between these phenotypes, we used GABAA receptor γ2 subunit heterozygous (γ2(+/-)) mice, which we previously characterized as a model animal with construct, face, and predictive validity for major depressive disorder. METHODS: To assess possible consequences of GABAergic deficits on glutamatergic transmission, we quantitated the cell surface expression of N-methyl-D-aspartate (NMDA)-type and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors and the function of synapses in the hippocampus and medial prefrontal cortex of γ2(+/-) mice. We also analyzed the effects of an acute dose of the experimental antidepressant ketamine on all these parameters in γ2(+/-) versus wild-type mice. RESULTS: Modest defects in GABAergic synaptic transmission of γ2(+/-) mice resulted in a strikingly prominent homeostatic-like reduction in the cell surface expression of NMDA-type and AMPA-type glutamate receptors, along with prominent functional impairment of glutamatergic synapses in the hippocampus and medial prefrontal cortex. A single subanesthetic dose of ketamine normalized glutamate receptor expression and synaptic function of γ2(+/-) mice to wild-type levels for a prolonged period, along with antidepressant-like behavioral consequences selectively in γ2(+/-) mice. The GABAergic synapses of γ2(+/-) mice were potentiated by ketamine in parallel but only in the medial prefrontal cortex. CONCLUSIONS: Depressive-like brain states that are caused by GABAergic deficits involve a homeostatic-like reduction of glutamatergic transmission that is reversible by an acute, subanesthetic dose of ketamine, along with regionally selective potentiation of GABAergic synapses. The data merge the GABAergic and glutamatergic deficit hypotheses of major depressive disorder.
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Mice carrying heterozygous deficiency of GABAAR γ2 subunit in forebrain display reduced surface expression of NMDA and AMPA receptor subunits in mPFC that could be restored via ketamine treatment.
“and the reduced surface expression of NMDA and AMPA receptor subunits in mPFC that could be restored via ketamine treatment 217”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [217]
GABAergic impairment could affect glutamatergic signaling in MDD PFC.
“suggesting that GABAergic impairment could affect glutamatergic signaling in MDD PFC.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [217]
Antidepressant treatment or increases in cellular activation reverses disease and stress-induced changes in GABAergic signaling.
“Conversely, antidepressant treatment or increases in cellular activation (through deep brain stimulation or optogenetic/pharmacological manipulations) reverses these disease and stress-induced changes in GABAergic signaling [123-127].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [126]
Anxiety- and despair-like behavior in γ2 knockdown mice is reversed with acute ketamine treatment.
“Global heterozygous knockdown of the γ2 subunit leads to impaired GABAergic signaling [11 ], as well as anxiety- and despair-like behavior that is reversed with chronic desipramine (but not fluoxetine) [127] and acute ketamine [126] treatment.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [126]
Ketamine administration to mice with a global reduction of GABAA receptor function reversed behavioral despair and novelty-induced hyper-anxiety and selectively potentiated GABAergic synaptic inhibition within the mPFC.
“In particular, ketamine administration to mice with a global reduction of GABAA receptor function, reversed behavioral despair and novelty-induced hyper-anxiety and selectively potentiated GABAergic synaptic inhibition within the mPFC 53.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [53]
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References 72 · Cited by 114
- Authors
- Ren, Z., Pribiag, H., Jefferson, S. J., Shorey, M., Fuchs, T., Stellwagen, D., & Luscher, B.
- Affiliations
- Pennsylvania State University (US)
- Montreal General Hospital (CA)
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 80
- Issue
- 6
- Pages
- 457-468
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4983262
- OpenAlex
- W2315792699
- Cited by
- 114
- References
- 72
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 10 · 2023: 19 · 2022: 6 · 2021: 14 · 2020: 10 · 2019: 19 · 2018: 9 · 2017: 7 · 2016: 6
- FWCI
- 11.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Mental Health (MH089111, MH099851)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- major depressive disorder, glutamatergic neurotransmission, ketamine, synaptic homeostasis, NMDA receptor, AMPA receptors, cell surface receptor expression, hippocampus, medial prefrontal cortex, antidepressant-like behavior
- MeSH terms
- Animals, Behavior, Animal, Major Depressive Disorder, gamma-Aminobutyric Acid, Hippocampus, Homeostasis, Ketamine, Receptors, GABA-A, Synapses, Down-Regulation, Receptors, N-Methyl-D-Aspartate, Prefrontal Cortex, Receptors, AMPA, Glutamic Acid, Mice
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