Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine
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Subanesthetic ketamine evokes rapid antidepressant effects in human patients that persist long past ketamine's chemical half-life of ~2 h. Ketamine's sustained antidepressant action may be due to modulation of cortical plasticity. We find that ketamine ameliorates depression-like behavior in the forced swim test in adult mice, and this depends on parvalbumin-expressing (PV) neuron-directed neuregulin-1 (NRG1)/ErbB4 signaling. Ketamine rapidly downregulates NRG1 expression in PV inhibitory neurons in mouse medial prefrontal cortex (mPFC) following a single low-dose ketamine treatment. This NRG1 downregulation in PV neurons co-tracks with the decreases in synaptic inhibition to mPFC excitatory neurons for up to a week. This results from reduced synaptic excitation to PV neurons, and is blocked by exogenous NRG1 as well as by PV targeted ErbB4 receptor knockout. Thus, we conceptualize that ketamine's effects are mediated through rapid and sustained cortical disinhibition via PV-specific NRG1 signaling. Our findings reveal a novel neural plasticity-based mechanism for ketamine's acute and long-lasting antidepressant effects.
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Low-dose ketamine treatment reduces L2/3 PV cell activity by reducing the strength of their L4 excitatory inputs, resulting in increases in excitatory neuron responses in L2/3 of bV1, consistent with a PV-mediated cortical disinhibitory mechanism.
“Low-dose ketamine treatment reduces L2/3 PV cell activity by reducing the strength of their L4 excitatory inputs, resulting in increases in excitatory neuron responses in L2/3 of bV1, consistent with a PV-mediated cortical disinhibitory mechanism (Grieco et al., 2020(Grieco et al., , 2021)).”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Grieco et al., 2021
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Johnston, K. G., Grieco, S. F., Zhang, H., Jin, S., Xu, X., & Nie, Q. (2021) · Cell Reports Methods · doi:10.1016/j.crmeth.2022.100207 · Cited by 11 · see citing works
Self-citationMechanism of saikogenin G against major depressive disorder determined by network pharmacology
Hu, L., Wang, J., Zhao, X., & Cai, D. (2022) · Medicine · doi:10.1097/md.0000000000030193 · Cited by 8 · see citing works
Choi, Y., Kim, B., Ham, S., Chung, S., Maeng, S., Kim, H.-S., & Im, H. (2021) · PLoS ONE · doi:10.1371/journal.pone.0256390 · Cited by 8 · see citing works
Xu, J.-J., Kan, W., Wang, T., Li, L., Zhang, Y., Ge, Z.-Y., Xu, J.-Y., Yin, Z.-J., Feng, Y., Wang, G., et al. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.05.038 · Cited by 7 · see citing works
Grice, A. B., Sloofman, L. G., Levy, T., Walker, H., Ganesh, G., Santos, M. R. D. L., Amini, P., Buxbaum, J. D., Kolevzon, A. L., Kostić, A., et al. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03005-8 · Cited by 5 · see citing works
Intranasal Delivery of Ketamine Induces Cortical Disinhibition
Qiao, X., Grieco, S. F., Yu, Z., Holmes, T. C., & Xu, X. (2023) · eNeuro · doi:10.1523/eneuro.0107-23.2023 · Cited by 2 · see citing works
Self-citationReceptor tyrosine kinases in major depressive disorder
Dakroub, F., El-Orfali, Y., Mantash, S., Alkalamouni, H., Dakroub, R., & Kobeissy, F. H. (2023) · Elsevier eBooks · doi:10.1016/b978-0-443-18677-6.00009-9 · Cited by 1 · see citing works
Lin, X., Chen, L., Baglietto‐Vargas, D., Ye, Q., LaFerla, F. M., Nitz, D. A., Holmes, T. C., & Xu, X. (2021) · Research Square · doi:10.21203/rs.3.rs-550358/v1
Self-citationEsketamine ameliorates depression-like behavior in mice via modulation of the NRG1–ErbB4 pathway
Yu, H., Zhu, Y., Wang, J., He, Y., Li, H., Li, S., Wang, N., Chen, N., Chen, J., Song, H., et al. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1722336
Li, Z., Si, T., Wu, Q.-R., Zhao, J.-H., Hua, W.-Z., Zhang, Y., Yang, S., Mao, Y.-Y., Zang, W., & Cao, J. (2026) · iScience · doi:10.1016/j.isci.2026.116454
- Authors
- Grieco, S. F., Qiao, X., Johnston, K. G., Chen, L., Nelson, R. R., Lai, C., Holmes, T. C., & Xu, X.
- Affiliations
- University of California, Irvine (US)
- Indiana University Bloomington (US)
- Corresponding author
- Xu, Xiangmin
- Venue
- Translational Psychiatry
- Published
- 2021-02-24
- Volume
- 11
- Issue
- 1
- Pages
- 144-144
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC7904825
- OpenAlex
- W3131262636
- Cited by
- 24
- References
- 73
- Citations by year
- 2026: 2 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 6
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH105427)
- U.S. Department of Health & Human Services | NIH | National Eye Institute (EY028212)
- 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
- subanesthetic ketamine, antidepressant effects, neuregulin-1, ERBB4 signaling, parvalbumin neurons, medial prefrontal cortex, cortical disinhibition, synaptic inhibition, depression-like behavior, forced swim test, cortical plasticity, inhibitory interneurons
- MeSH terms
- Animals, Antidepressive Agents, Humans, Ketamine, Neuronal Plasticity, Parvalbumins, Neuregulin-1, Mice, Receptor, ErbB-4
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