KCNQ channel openers reverse depressive symptoms via an active resilience mechanism

Allyson K. Friedman, Barbara Juarez, Stacy M. Ku, Hongxing Zhang, Rhodora C. Calizo, Jessica J. Walsh, Dipesh Chaudhury, Song Zhang, Angel Hawkins, David M. Dietz, James W. Murrough, Maria Ribadeneira, Erik H. Wong, Rachael L. Neve, Ming Hu Han

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number11671
JournalNature communications
Volume7
DOIs
StatePublished - May 24 2016

    Fingerprint

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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. (2016). KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nature communications, 7, [11671]. https://doi.org/10.1038/ncomms11671