期刊
NEUROBIOLOGY OF DISEASE
卷 35, 期 1, 页码 91-102出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2009.04.007
关键词
Sodium channel; SCN1A; GEFS; SMEI; Epilepsy; Mutation
资金
- NIH [NS046484, NS051834, NS48336]
- March of Dimes Birth Defects Foundation [5-FY02-250]
- McKnight Endowment Fund for Neuroscience
- European Integrated Project EPICURE (M.M.)
- Italian Telethon [GGP07277]
- Epilepsy Foundation
- AFIP
- FAPESP [07-50534-5, 98/14303-3]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [98/14303-3] Funding Source: FAPESP
Mutations in the voltage-gated sodium channel SCN1A are responsible for a number of seizure disorders including Generalized Epilepsy with Febrile Seizures Plus (GEFS+) and Severe Myoclonic Epilepsy of Infancy (SMEI). To determine the effects of SCN1A mutations on channel function in vivo, we generated a bacterial artificial chromosome (BAC) transgenic mouse model that expresses the human SCN1A GEFS+ mutation, R1648H. Mice with the R1648H mutation exhibit a more severe response to the proconvulsant kainic acid compared with mice expressing a control Scn1a transgene. Electrophysiological analysis of dissociated neurons from mice with the R1648H mutation reveal delayed recovery from inactivation and increased use-dependent inactivation only in inhibitory bipolar neurons, as well as a hyperpolarizing shift in the voltage dependence of inactivation only in excitatory pyramidal neurons. These results demonstrate that the effects of SCN1A mutations are cell type-dependent and that the R1648H mutation specifically leads to a reduction in interneuron excitability. (C) 2009 Elsevier Inc. All rights reserved.
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