학술논문
Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2.
Document Type
Academic Journal
Author
Lopez JP; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Lücken MD; Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764 Bavaria, Germany.; Brivio E; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Karamihalev S; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Kos A; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; De Donno C; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany; Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764 Bavaria, Germany.; Benjamin A; Department of Brain Sciences, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot 76100, Israel.; Yang H; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Dick ALW; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Stoffel R; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Flachskamm C; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Ressle A; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Roeh S; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Huettl RE; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Parl A; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Eggert C; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Novak B; Proteomics and Biomarkers, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Yan Y; Proteomics and Biomarkers, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Yeoh K; Proteomics and Biomarkers, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Holzapfel M; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Hauger B; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Harbich D; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Schmid B; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Di Giaimo R; Department of Developmental Neurobiology, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Turck CW; Proteomics and Biomarkers, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Schmidt MV; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Deussing JM; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Eder M; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany.; Dine J; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany; Department of Brain Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.; Theis FJ; Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764 Bavaria, Germany.; Chen A; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804 Bavaria, Germany; Department of Brain Sciences, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: alon.chen@weizmann.ac.il.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 8809320 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4199 (Electronic) Linking ISSN: 08966273 NLM ISO Abbreviation: Neuron Subsets: MEDLINE
Subject
Language
English
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.
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.)
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.)