Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome.

Christine S. Cheah, Frank H. Yu, Ruth E. Westenbroek, Franck K. Kalume, John C. Oakley, Gregory Potter, John L. Rubenstein, William A. Catterall

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Heterozygous loss-of-function mutations in the brain sodium channel Na(V)1.1 cause Dravet syndrome (DS), a pharmacoresistant infantile-onset epilepsy syndrome with comorbidities of cognitive impairment and premature death. Previous studies using a mouse model of DS revealed reduced sodium currents and impaired excitability in GABAergic interneurons in the hippocampus, leading to the hypothesis that impaired excitability of GABAergic inhibitory neurons is the cause of epilepsy and premature death in DS. However, other classes of GABAergic interneurons are less impaired, so the direct cause of hyperexcitability, epilepsy, and premature death has remained unresolved. We generated a floxed Scn1a mouse line and used the Cre-Lox method driven by an enhancer from the Dlx1,2 locus for conditional deletion of Scn1a in forebrain GABAergic neurons. Immunocytochemical studies demonstrated selective loss of Na(V)1.1 channels in GABAergic interneurons in cerebral cortex and hippocampus. Mice with this deletion died prematurely following generalized tonic-clonic seizures, and they were equally susceptible to thermal induction of seizures as mice with global deletion of Scn1a. Evidently, loss of Na(V)1.1 channels in forebrain GABAergic neurons is both necessary and sufficient to cause epilepsy and premature death in DS.

Original languageEnglish (US)
Pages (from-to)14646-14651
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number36
StatePublished - Sep 4 2012
Externally publishedYes

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Myoclonic Epilepsy
Premature Mortality
Sodium Channels
Interneurons
GABAergic Neurons
Cause of Death
Epilepsy
Seizures
Prosencephalon
Hippocampus
Cerebral Cortex
Comorbidity
Hot Temperature
Sodium
Mutation
Brain

ASJC Scopus subject areas

  • General

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Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome. / Cheah, Christine S.; Yu, Frank H.; Westenbroek, Ruth E.; Kalume, Franck K.; Oakley, John C.; Potter, Gregory; Rubenstein, John L.; Catterall, William A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 36, 04.09.2012, p. 14646-14651.

Research output: Contribution to journalArticle

Cheah, CS, Yu, FH, Westenbroek, RE, Kalume, FK, Oakley, JC, Potter, G, Rubenstein, JL & Catterall, WA 2012, 'Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome.', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 36, pp. 14646-14651.
Cheah, Christine S. ; Yu, Frank H. ; Westenbroek, Ruth E. ; Kalume, Franck K. ; Oakley, John C. ; Potter, Gregory ; Rubenstein, John L. ; Catterall, William A. / Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 36. pp. 14646-14651.
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