title: Insights into pathophysiology and therapy from a mouse model of Dravet syndrome.
abstract: Mutations in voltage-gated sodium channels are associated with epilepsy syndromes with a wide range of severity. Complete loss of function in the Na(v) 1.1 channel encoded by the SCN1A gene is associated with severe myoclonic epilepsy in infancy (SMEI), a devastating infantile-onset epilepsy with ataxia, cognitive dysfunction, and febrile and afebrile seizures resistant to current medications. Genetic mouse models of SMEI have been created that strikingly recapitulate the SMEI phenotype including age and temperature dependence of seizures and ataxia. Loss-of-function in Na(v) 1.1 channels results in severely impaired sodium current and action potential firing in hippocampal γ-aminobutyric acid (GABA)ergic interneurons without detectable changes in excitatory pyramidal neurons. The resulting imbalance between excitation and inhibition likely contributes to hyperexcitability and seizures. Reduced sodium current and action potential firing in cerebellar Purkinje neurons likely contributes to comorbid ataxia. A mechanistic understanding of hyperexcitability, seizures, and comorbidities such as ataxia has led to novel strategies for treatment.
authors.affiliation: Department of Pharmacology Neurology, University of Washington, Seattle, Washington 98195-7280, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Oakley
authors.forename: Franck
authors.initials: F
authors.lastname: Kalume
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D006801:Humans; D051379:Mice; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics; D013577:Syndrome
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; D015222:Sodium Channels