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Insights into pathophysiology and therapy from a mouse model of Dravet syndrome
Author(s) -
Oakley John C.,
Kalume Franck,
Catterall William A.
Publication year - 2011
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2011.03004.x
Subject(s) - dravet syndrome , ataxia , epilepsy , myoclonic epilepsy , neuroscience , sodium channel , cerebellar ataxia , medicine , excitatory postsynaptic potential , anticonvulsant , hippocampal formation , psychology , inhibitory postsynaptic potential , chemistry , sodium , organic chemistry
Summary 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.