Article

A knock-in model of human epilepsy in Drosophila reveals a novel cellular mechanism associated with heat-induced seizure.

Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697-1280, and Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912.
Journal of Neuroscience (Impact Factor: 6.75). 10/2012; 32(41):14145-55. DOI: 10.1523/JNEUROSCI.2932-12.2012
Source: PubMed

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.

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