Specific deletion of Na V 1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome
- 20 August 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (36), 14646-14651
- https://doi.org/10.1073/pnas.1211591109
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.This publication has 30 references indexed in Scilit:
- Pure haploinsufficiency for Dravet syndrome NaV1.1 (SCN1A) sodium channel truncating mutationsEpilepsia, 2011
- Sodium channel gene family: epilepsy mutations, gene interactions and modifier effectsJournal Of Physiology-London, 2010
- NaV1.1 channels and epilepsyJournal Of Physiology-London, 2010
- Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancyProceedings of the National Academy of Sciences of the United States of America, 2009
- Generation of Cre-transgenic mice using Dlx1/Dlx2 enhancers and their characterization in GABAergic interneuronsMolecular and Cellular Neuroscience, 2009
- Dlx1&2 and Mash1 transcription factors control striatal patterning and differentiation through parallel and overlapping pathwaysJournal of Comparative Neurology, 2008
- Inherited Neuronal Ion Channelopathies: New Windows on Complex Neurological DiseasesJournal of Neuroscience, 2008
- Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in InfancyJournal of Neuroscience, 2007
- Severe myoclonic epilepsy in infants – a review based on the Tokyo Women's Medical University series of 84 casesBrain & Development, 2001
- De Novo Mutations in the Sodium-Channel Gene SCN1A Cause Severe Myoclonic Epilepsy of InfancyAmerican Journal of Human Genetics, 2001