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

Neuron. 2022 Jul 20;110(14):2283-2298.e9. doi: 10.1016/j.neuron.2022.05.001. Epub 2022 May 31.


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.

Keywords: KCNQ; KCNQ2; cell-type specific; ezogabine; glutamatergic neurons; ketamine; retigabine; single-cell RNA sequencing; sustained antidepressant response; ventral hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Hippocampus
  • KCNQ2 Potassium Channel / genetics
  • Ketamine* / pharmacology
  • Ketamine* / therapeutic use
  • Mice
  • Nerve Tissue Proteins
  • Neurons


  • Antidepressive Agents
  • KCNQ2 Potassium Channel
  • Kcnq2 protein, mouse
  • Nerve Tissue Proteins
  • Ketamine