A knock-in model of human epilepsy in Drosophila reveals a novel cellular mechanism associated with heat-induced seizure.
J Neurosci
; 32(41): 14145-55, 2012 Oct 10.
Article
em En
| MEDLINE
| ID: mdl-23055484
ABSTRACT
Over 40 missense mutations in the human SCN1A sodium channel gene are linked to an epilepsy syndrome termed genetic epilepsy with febrile seizures plus (GEFS+). Inheritance of GEFS+ is dominant, but the underlying cellular mechanisms remain poorly understood. Here we report that knock-in of a GEFS+ SCN1A mutation (K1270T) into the Drosophila sodium channel gene, para, causes a semidominant temperature-induced seizure phenotype. Electrophysiological studies of GABAergic interneurons in the brains of adult GEFS+ flies reveal a novel cellular mechanism underlying heat-induced seizures the deactivation threshold for persistent sodium currents reversibly shifts to a more negative voltage when the temperature is elevated. This leads to sustained depolarizations in GABAergic neurons and reduced inhibitory activity in the central nervous system. Furthermore, our data indicate a natural temperature-dependent shift in sodium current deactivation (exacerbated by mutation) may contribute to febrile seizures in GEFS+ and perhaps normal individuals.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Epilepsia Generalizada
/
Convulsões Febris
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Modelos Animais de Doenças
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Técnicas de Introdução de Genes
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Canal de Sódio Disparado por Voltagem NAV1.1
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Temperatura Alta
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Animals
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Female
/
Humans
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Male
Idioma:
En
Revista:
J Neurosci
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos