Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2
Lopez JP, Luecken MD, Brivio E, Karamihalev S, Kos A, De Donno C, Benjamin A, Yang H, Dick ALW, Stoffel R, Flachskamm C, Ressle A, Roeh S, Huettl RE, Parl A, Eggert C, Novak B, Yan Y, Yeoh K, Holzapfel M, Hauger B, Harbich D, Schmid B, Di Giaimo R, Turck CW, Schmidt M, Deussing JM, Eder M, Dine J, Theis FJ, Chen A (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 110
Pages Range: 2283-2298.e9
Journal Issue: 14
DOI: 10.1016/j.neuron.2022.05.001
Abstract
A single sub-anesthetic dose of ketamine produces a rapid and sustained antidepressant response, yet the molecular mechanisms responsible for this remain unclear. Here, we identified cell-type-specific transcriptional signatures associated with a sustained ketamine response in mice. Most interestingly, we identified the Kcnq2 gene as an important downstream regulator of ketamine action in glutamatergic neurons of the ventral hippocampus. We validated these findings through a series of complementary molecular, electrophysiological, cellular, pharmacological, behavioral, and functional experiments. We demonstrated that adjunctive treatment with retigabine, a KCNQ activator, augments ketamine's antidepressant-like effects in mice. Intriguingly, these effects are ketamine specific, as they do not modulate a response to classical antidepressants, such as escitalopram. These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.
Involved external institutions
Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie)
Germany (DE)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Weizmann Institute of Science
Israel (IL)
Germany (DE)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Weizmann Institute of Science
Israel (IL)
How to cite
APA:
Lopez, J.P., Luecken, M.D., Brivio, E., Karamihalev, S., Kos, A., De Donno, C.,... Chen, A. (2022). Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2. Neuron, 110(14), 2283-2298.e9. https://doi.org/10.1016/j.neuron.2022.05.001
MLA:
Lopez, Juan Pablo, et al. "Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2." Neuron 110.14 (2022): 2283-2298.e9.
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