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GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions
Open accessAbstract
A single subanesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates this increase and ketamine's behavioral actions has not been identified. To address this question, we used a combination of viral shRNA and conditional mutation to produce cell-specific knockdown or deletion of a key NMDAR subunit, GluN2B, implicated in the actions of ketamine. The results demonstrated that the antidepressant actions of ketamine were blocked by GluN2B-NMDAR knockdown on GABA (Gad1) interneurons, as well as subtypes expressing somatostatin (Sst) or parvalbumin (Pvalb), but not glutamate principle neurons in the medial prefrontal cortex (mPFC). Further analysis of GABA subtypes showed that cell-specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons. These findings demonstrate that GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for the rapid antidepressant actions of ketamine and show sex-specific adaptive mechanisms to GluN2B modulation.
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“This behavioral effect corresponded to a disinhibition of layer 5 mPFC pyramidal neurons whereby inhibition of GABA signaling strengthened pyramidal neuron activity.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Gerhard et al., 2020
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“The genetic manipulation alone appeared to reduce immobility relative to controls to a point where ketamine could not elicit a further reduction.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Gerhard et al., 2020
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“using a genetic knockdown approach in mice found that loss of GluN2B in medial PFC (mPFC GABAergic interneurons, and specifically in those expressing somatostatin (SST) and parvalbumin (PV), occluded the antidepressant-like effects of ketamine in the forced swim test (Gerhard et al., 2020).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Gerhard et al., 2020
In the citing paper
“Furthermore, knock-down and deletion of critical ketaminesensitive NMDARs from either somatostatin-or parvalbuminexpressing interneurons alters baseline behaviors in the FST and other tasks and eliminates the ability of ketamine to change these behaviors in unstressed mice [210].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [210]
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“Furthermore, knock-down and deletion of critical ketaminesensitive NMDARs from either somatostatin-or parvalbuminexpressing interneurons alters baseline behaviors in the FST and other tasks and eliminates the ability of ketamine to change these behaviors in unstressed mice [210].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [210]
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“As in the hippocampus, ketamine inhibits the discharge of interneurons in the PFC and reduces spontaneous IPSCs in pyramidal cells acutely [210], while restoring inhibition at later timepoints corresponding to its behavioral actions [211].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [210]
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Metadata
- Authors
- Gerhard, D. M., Pothula, S., Liu, R.-J., Wu, M., Li, X.-Y., Girgenti, M. J., Taylor, S. R., Duman, C. H., Delpire, E., Picciotto, M., Wohleb, E. S., & Duman, R. S.
- Affiliations
- Yale University (US)
- Vanderbilt University (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2020-01-27
- Volume
- 130
- Issue
- 3
- Pages
- 1336-1349
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC7269589
- OpenAlex
- W2991582092
- Cited by
- 345
- References
- 61
- Citations by year
- 2026: 37 · 2025: 51 · 2024: 51 · 2023: 61 · 2022: 55 · 2021: 44 · 2020: 43
- FWCI
- 22.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH093897, MH105910, MH077681)
- National Institute on Drug Abuse (DA14241)
- National Institute on Alcohol Abuse and Alcoholism (AA013514)
- 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
- ketamine, rapid antidepressant effects, GABAergic interneurons, GluN2B, NMDA receptor, somatostatin interneurons, parvalbumin interneurons, medial prefrontal cortex, depression, sex differences, excitatory postsynaptic currents, glutamate release, synaptic plasticity
- MeSH terms
- Animals, Antidepressive Agents, Female, Glutamate Decarboxylase, Interneurons, Ketamine, Male, Mice, Transgenic, Parvalbumins, Sex Characteristics, Somatostatin, Receptors, N-Methyl-D-Aspartate, Mice, Gene Knockout Techniques, GABAergic Neurons
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