Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome

Christine S. Cheah, Ruth E. Westenbroek, William H. Roden, Franck Kalume, John C. Oakley, Laura A. Jansen, William A. Catterall

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Dravet Syndrome (DS) is an intractable genetic epilepsy caused by loss-of-function mutations in SCN1A, the gene encoding brain sodium channel Nav1.1. DS is associated with increased frequency of sudden unexpected death in humans and in a mouse genetic model of this disease. Here we correlate the time course of declining expression of the murine embryonic sodium channel Nav1.3 and the rise in expression of the adult sodium channel Nav1.1 with susceptibility to epileptic seizures and increased incidence of sudden death in DS mice. Parallel studies with unaffected human brain tissue demonstrate similar decline in Nav1.3 and increase in Nav1.1 with age. In light of these results, we introduce the hypothesis that the natural loss Nav1.3 channel expression in brain development, coupled with the failure of increase in functional Na v1.1 channels in DS, defines a tipping point that leads to disinhibition of neural circuits, intractable seizures, co-morbidities, and premature death in this disease.

Original languageEnglish
Article numbera10
JournalChannels
Volume7
Issue number6
DOIs
StatePublished - Jan 1 2013

Keywords

  • Dravet syndrome
  • Epilepsy
  • Ion channel
  • Premature death
  • Seizure
  • Sodium channel

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    Cheah, C. S., Westenbroek, R. E., Roden, W. H., Kalume, F., Oakley, J. C., Jansen, L. A., & Catterall, W. A. (2013). Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome. Channels, 7(6), [a10]. https://doi.org/10.4161/chan.26023