A BAC transgenic mouse model reveals neuron subtype-specific effects of a Generalized Epilepsy with Febrile Seizures Plus (GEFS plus ) mutation

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.This study was supported by NIH Research Grants NS046484, NS051834 (A.E.) and NS48336 (A.L.G.), and grants from the March of Dimes Birth Defects Foundation (#5-FY02-250) (A.E.) and the McKnight Endowment Fund for Neuroscience (A.L.G.), the European Integrated Project EPICURE (M.M.) and the Italian Telethon grant GGP07277 (M.M.). K.D. was supported by a fellowship from the Epilepsy Foundation. L.P. was supported fellowships from AFIP and FAPESP (07-50534-5). ST was supported by FAPESP (CEPID#98/14303-3)