Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses

Fogaça, Manoela V.; Wu, Min; Li, Chan; Li, Xiao-Yuan; Picciotto, Marina R.; Duman, Ronald S.

doi:10.1038/s41380-020-00916-y

Cited by 129Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses

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Fogaça, Manoela V., Wu, Min, Li, Chan, Li, Xiao-Yuan, Picciotto, Marina R., Duman, Ronald S.·2021·Molecular Psychiatry

DOI 10.1038/s41380-020-00916-yPMC PMC8052382

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Abstract

Major depressive disorder (MDD) is associated with alterations of GABAergic interneurons, notably somatostatin (Sst) as well as parvalbumin (Pvalb), in cortical brain areas. In addition, the antidepressant effects of rapid-acting drugs are thought to occur via inhibition of GABA interneurons. However, the impact of these interneuron subtypes in affective behaviors as well as in the effects of rapid-acting antidepressants remains to be determined. Here, we used a Cre-dependent DREADD-chemogenetic approach to determine if inhibition of GABA interneurons in the mPFC of male mice is sufficient to produce antidepressant actions, and conversely if activation of these interneurons blocks the rapid and sustained antidepressant effects of scopolamine, a nonselective acetylcholine muscarinic receptor antagonist. Chemogenetic inhibition of all GABA interneurons (Gad1+), as well as Sst+ and Pvalb+ subtypes in the mPFC produced dose and time-dependent antidepressant effects in the forced swim and novelty suppressed feeding tests, and increased synaptic plasticity. In contrast, stimulation of Gad1, Sst, or Pvalb interneurons in mPFC abolished the effects of scopolamine and prevented scopolamine induction of synaptic plasticity. The results demonstrate that transient inhibition of GABA interneurons promotes synaptic plasticity that underlies rapid antidepressant responses.

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Chemogenetic inhibition of somatostatin- and parvalbumin-expressing interneurons in the medial prefrontal cortex mimics antidepressant effects in the forced swim test and other tasks.
“Similarly, chemogenetic inhibition of either somatostatin-and parvalbumin-expressing interneurons in the mPFC mimicked the effects produced by antidepressants in the FST and other tasks, suggesting that transient inhibition of GABAergic interneurons contributes to the actions of rapidly”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [212]
Transient inhibition of GABAergic interneurons contributes to the actions of rapidly acting antidepressants.
“Similarly, chemogenetic inhibition of either somatostatin-and parvalbumin-expressing interneurons in the mPFC mimicked the effects produced by antidepressants in the FST and other tasks, suggesting that transient inhibition of GABAergic interneurons contributes to the actions of rapidly”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [212]

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Age- and sex-specific effects of stress on parvalbumin interneurons in preclinical models: Relevance to sex differences in clinical neuropsychiatric and neurodevelopmental disorders
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Integrated analysis of the chemical-material basis and molecular mechanisms for the classic herbal formula of Lily Bulb and Rehmannia Decoction in alleviating depression
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Baihe Dihuang (Lilium Henryi Baker and Rehmannia Glutinosa) decoction attenuates somatostatin interneurons deficits in prefrontal cortex of depression via miRNA-144–3p mediated GABA synthesis and release
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Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels
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The Hypothalamic-Pituitary-Gonadal Axis in Men with Schizophrenia
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A visual cortical-lateral posterior thalamic nucleus circuit regulates depressive-like behaviors in male mice
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Natural product Kaji-ichigoside F1 exhibits rapid antidepression via activating the AMPA–BDNF–mTOR pathway and inhibiting the NMDAR–CaMKIIα pathway
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Advancing Neuroscience and Therapy: Insights into Genetic and Non-Genetic Neuromodulation Approaches
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Emerging Medications for Treatment-Resistant Depression: A Review with Perspective on Mechanisms and Challenges
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The Role of Extrasynaptic GABA Receptors in Postpartum Depression
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Distinct ACC Neural Mechanisms Underlie Authentic and Transmitted Anxiety Induced by Maternal Separation in Mice
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Choice impulsivity after repeated social stress is associated with increased perineuronal nets in the medial prefrontal cortex
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Basmisanil, an α5-GABAAR negative allosteric modulator, produces rapid and sustained antidepressant-like responses in male mice
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Fast-spiking parvalbumin-positive interneurons: new perspectives of treatment and future challenges in dementia
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Decreased phase information transfer from the mPFC to the BLA: During exploratory behavior in CUMS rats
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Prenatal psychological stress mediates vertical transmission of gut microbiome to the next generation affecting offspring depressive-like behaviors and neurotransmitter
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Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets
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Defects of parvalbumin-positive interneurons are implicated in psychiatric disorders
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Cav3.1 T‐Type Calcium Channel Acts as a Gateway for GABAergic Excitation in the Medial Prefrontal Cortex That Leads to Chronic Psychological Stress Responses in Mice
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(-)-Syringaresinol Exerts an Antidepressant-like Activity in Mice by Noncompetitive Inhibition of the Serotonin Transporter
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Prefrontal ErbB4-positive interneurons for avoidance
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AI Machine Learning Technique Characterizes Potential Markers of Depression in Two Animal Models of Depression
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Single-Nucleus Transcriptomics of the Nucleus Accumbens Reveals Cell-Type-Specific Dysregulation in Adolescent Macaques with Depressive-Like Behaviors
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Inhibition of SERT and NMDAR synergistically confers rapid antidepressant effects of ketamine
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Authors: Fogaça, M. V., Wu, M., Li, C., Li, X.-Y., Picciotto, M. R., & Duman, R. S.
Affiliations: Yale University (US)
Corresponding author: Fogaça, Manoela V.
ORCID: Fogaça, Manoela V.
Wu, Min
Li, Chan
Picciotto, Marina R.
Duman, Ronald S.
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2020-10-17
Volume: 26
Issue: 7
Pages: 3277-3291
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/s41380-020-00916-y
PMC: PMC8052382
OpenAlex: W3093084992
Cited by: 129
References: 63
Citations by year: 2026: 27 · 2025: 31 · 2024: 17 · 2023: 26 · 2022: 19 · 2021: 9
FWCI: 8.09
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Molecular Psychiatry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH093897, MH105910)
Topics: Health Sciences › Medicine › Pharmacology › 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: GABAergic interneurons, medial prefrontal cortex, major depressive disorder, rapid-acting antidepressants, scopolamine, somatostatin interneurons, parvalbumin interneurons, GAD1, synaptic plasticity, chemogenetic inhibition, forced swim test, novelty-suppressed feeding, depression
MeSH terms: Animals, Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, gamma-Aminobutyric Acid, Interneurons, Male, Parvalbumins, Prefrontal Cortex, Mice

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Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses

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