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Lopez, J.P.* ; Luecken, M. ; Brivio, E.* ; Karamihalev, S.* ; Kos, A.* ; De Donno, C. ; Benjamin, A.* ; Yang, H.* ; Dick, A.L.W.* ; Stoffel, R.* ; Flachskamm, C.* ; Ressle, A.* ; Roeh, S.* ; Huettl, R.E.* ; Parl, A.* ; Eggert, C.* ; Novak, B.* ; Yan, Y.* ; Yeoh, K.* ; Holzapfel, M.* ; Hauger, B.* ; Harbich, D.* ; Schmid, B.* ; Di Giaimo, R.* ; Turck, C.W.* ; Schmidt, M.V.* ; Deussing, J.M.* ; Eder, M.* ; Dine, J.* ; Theis, F.J. ; Chen, A.*

Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2.

Neuron 110, 2283-2298.e9 (2022)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Kcnq ; Kcnq2 ; Cell-type Specific ; Ezogabine ; Glutamatergic Neurons ; Ketamine ; Retigabine ; Single-cell Rna Sequencing ; Sustained Antidepressant Response ; Ventral Hippocampus
ISSN (print) / ISBN 0896-6273
e-ISSN 1097-4199
Journal Neuron
Quellenangaben Volume: 110, Issue: 14, Pages: 2283-2298.e9 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)