The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
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]
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The mouse brain in stereotaxic coordinates
Konsman, J. (2003) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(03)00088-x · Cited by 16,796
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,526
Antidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856
Interneurons of the neocortical inhibitory system
Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., & Wu, C. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1519 · Cited by 2,954
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata, M., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2010) · Science · doi:10.1126/science.1190287 · Cited by 2,881
Self-citationRational siRNA design for RNA interference
Reynolds, A., Leake, D., Boese, Q., Scaringe, S., Marshall, W. S., & Khvorova, A. (2004) · Nature Biotechnology · doi:10.1038/nbt936 · Cited by 2,094
GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits
Tremblay, R., Lee, S., & Rudy, B. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.033 · Cited by 2,033
NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses
Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P.-F., Kavalali, E. T., & Monteggia, L. M. (2011) · Nature · doi:10.1038/nature10130 · Cited by 1,926
Moghaddam, B., Adams, B., Verma, A., & Daly, D. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-08-02921.1997 · Cited by 1,793
Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants
Duman, R. S., Aghajanian, G. K., Sanacora, G., & Krystal, J. H. (2016) · Nature Medicine · doi:10.1038/nm.4050 · Cited by 1,750
Self-citation
Research works printed but not linked: 1
- 10.1016/j.nbd.2019 · DOI
Cited by
Sorted by citations
Prefrontal cortex and depression
Pizzagalli, D. A., & Roberts, A. C. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-021-01101-7 · Cited by 667
Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action
Castrén, E., & Monteggia, L. M. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.05.008 · Cited by 540
Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics
Aleksandrova, L. R., & Phillips, A. G. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.08.003 · Cited by 276
Ketamine and rapid antidepressant action: New treatments and novel synaptic signaling mechanisms
Krystal, J. H., Kavalali, E. T., & Monteggia, L. M. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-023-01629-w · Cited by 262
Ketamine: A tale of two enantiomers
Jelen, L. A., Young, A. H., & Stone, J. M. (2020) · Journal of Psychopharmacology · doi:10.1177/0269881120959644 · Cited by 266
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
