title: KCNQ channel openers reverse depressive symptoms via an active resilience mechanism.
abstract: Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K(+)) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K(+) channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Biological Sciences, Hunter College, Biology and Biochemistry PhD Program, Graduate Center, The City University of New York, New York, New York 10065, USA.
authors.forename: Allyson K
authors.identifier: http://orcid.org/0000-0002-8190-3011
authors.initials: AK
authors.lastname: Friedman
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Juarez
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Ku
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Rhodora C
authors.initials: RC
authors.lastname: Calizo
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Walsh
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Dipesh
authors.initials: D
authors.lastname: Chaudhury
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Angel
authors.initials: A
authors.lastname: Hawkins
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Murrough
authors.affiliation: CNS Pain Innovative Medicine Unit, AstraZeneca Pharmaceuticals, Wilmington, Delaware 19850, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Ribadeneira
authors.affiliation: CNS Pain Innovative Medicine Unit, AstraZeneca Pharmaceuticals, Wilmington, Delaware 19850, USA.
authors.forename: Erik H
authors.initials: EH
authors.lastname: Wong
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
mesh_terms: D000223:Adaptation, Psychological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D055724:Electrophysiological Phenomena; D006801:Humans; D051659:KCNQ3 Potassium Channel / Q000378:metabolism*; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D010655:Phenylenediamines / Q000494:pharmacology / Q000627:therapeutic use; D055500:Resilience, Psychological / Q000187:drug effects*; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; D002219:Carbamates; D051659:KCNQ3 Potassium Channel; C496917:Kcnq3 protein, mouse; D049990:Membrane Transport Modulators; D010655:Phenylenediamines; C101866:ezogabine