KCNQ channel openers reverse depressive symptoms via an active resilience mechanism
Open accessAbstract
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.
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Following chronic social defeat stress, stress-susceptible animals have increased ventral tegmental area dopamine neuron firing that persists for several weeks after stress termination.
“Following CSDS, stress-susceptible animals have increased VTA dopamine neuron firing [13, 23–29] that persists for several weeks after stress termination [28].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [25]
Chronic physical or psychosocial stressors increase ventral tegmental area dopamine neuron activity to elicit depression-like behavior.
“Chronic physical or psychosocial stressors increase VTA dopamine neuron activity to elicit depression-like behavior.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [25]
KCNQ overexpression or administration of KCNQ-openers rescues depressive behavior by reducing firing of nucleus accumbens projecting, but not prefrontal cortex projecting, ventral tegmental area dopamine neurons.
“KCNQ overexpression or administration of KCNQ-openers rescues depressive behavior [25, 27] by reducing firing of NAc projecting, but not PFC projecting VTA dopamine neurons [25].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [25]
Ih potentiation with repeated lamotrigine increases K+ currents and decreases neuronal excitability in previously susceptible mice to reverse social and sucrose preference deficits.
“Ih potentiation with repeated lamotrigine increases K+ currents and decreases neuronal excitability in previously susceptible mice to reverse social and sucrose preference deficits [25].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [25]
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References 41 · Cited by 172
- Authors
- Friedman, A. K., Juarez, B., Ku, S. M., Zhang, H., Calizo, R. C., Walsh, J. J., Chaudhury, D., Zhang, S., Hawkins, A., Dietz, D. M., Murrough, J. W., Ribadeneira, M., Wong, E. H., Neve, R. L., & Han, M.-H.
- Affiliations
- City University of New York (US)
- Icahn School of Medicine at Mount Sinai (US)
- AstraZeneca (United States) (US)
- McGovern Institute for Brain Research (US)
- Corresponding author
- Han, Ming-Hu
- ORCID
- Venue
- Nature Communications
- Published
- 2016-05-24
- Volume
- 7
- Issue
- 1
- Pages
- 11671-11671
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4890180
- OpenAlex
- W2408529313
- Cited by
- 172
- References
- 41
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 18 · 2023: 10 · 2022: 24 · 2021: 19 · 2020: 13 · 2019: 18 · 2018: 12 · 2017: 15 · 2016: 1
- FWCI
- 12.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CUNY Academic Works (City University of New York) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Nature
- Funders
- International Mental Health Research Organization
- National Alliance for Research on Schizophrenia and Depression
- Attias Family Foundation
- National Institute on Alcohol Abuse and Alcoholism (R01AA022445, F31AA022862)
- National Institute of Mental Health (F31MH108326, R21MH112081, MH092306, P50MH096890, R01MH092306, F31MH095425, F32MH096464, T32MH087004)
- National Institute on Minority Health and Health Disparities (MD007599, G12MD007599)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- KCNQ channels, potassium channel openers, retigabine, ezogabine, major depressive disorder, antidepressant efficacy, chronic social defeat stress, ventral tegmental area, dopaminergic neurons, neuronal hyperactivity
- MeSH terms
- Adaptation, Psychological, Animals, Antidepressive Agents, Behavior, Animal, Carbamates, Depressive Disorder, Major, Major Depressive Disorder, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Phenylenediamines, Stress, Psychological, Ventral Tegmental Area, Membrane Transport Modulators, Mice, KCNQ3 Potassium Channel, Resilience, Psychological, Electrophysiological Phenomena, Dopaminergic Neurons
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