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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., Competing Interests: Declaration of interests A.C. and J.P.L. are named on a patent pending for the combined use of retigabine (ezogabine) and ketamine to amplify antidepressant effects to treat depression and related conditions. F.J.T. reports receiving consulting fees from Roche Diagnostics GmbH and Cellarity Inc. and ownership interest in Cellarity, Inc. and Dermagnostix. All other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)