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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine Retigabine Escitalopram |
| Dose | single sub-anesthetic dose |
| Topics | Esketamine Ketamine |
| Citations | 78 |
| Key points | 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.