Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2.
J. Lopez, M. Lücken, E. Brivio, Stoyo Karamihalev, A. Kos, Carlo de Donno, Asaf Benjamin, Huanqing Yang, Alec L W Dick, R. Stoffel, C. Flachskamm, Andrea Ressle, Simone Roeh, R. Huettl, Andrea Parl, Carola Eggert, B. Novak, Yu Yan, K. Yeoh, Maria Holzapfel, B. Hauger, D. Harbich, B. Schmid, R. D. Giaimo, C. Turck, M. Schmidt, J. Deussing, M. Eder, J. Dine, F. Theis, Alon Chen
Neuron May 1, 2022 DOI: 10.1016/j.neuron.2022.05.001 via Semantic Scholar
Summary
A single low dose of ketamine produces a rapid and lasting antidepressant effect in mice, but the molecular mechanisms are unclear. This work identifies Kcnq2 gene activity in glutamatergic neurons of the ventral hippocampus as a key regulator of ketamine's sustained action. Combining ketamine with retigabine, a KCNQ activator, enhanced antidepressant-like effects, an effect not seen with the classical antidepressant escitalopram. These findings advance understanding of ketamine's sustained antidepressant mechanisms and suggest potential clinical applications.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Keywords | Medicine |
| Citations | 78 |
| Key finding | Kcnq2 gene in glutamatergic neurons of the ventral hippocampus regulates ketamine's sustained antidepressant effects, and adjunctive retigabine augments these effects specifically for ketamine, not escitalopram. |
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.