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

Bin Tang, Karoni Dutt, Ligia Papale, Raffaella Rusconi, Anupama Shankar, Jessica Hunter, Sergio Tufik, Frank H. Yu, William A. Catterall, Massimo Mantegazza, Alan L. Goldin, Andrew Escayg

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)91-102
Number of pages12
JournalNeurobiology of Disease
Volume35
Issue number1
DOIs
Publication statusPublished - Jul 2009

Keywords

  • Epilepsy
  • GEFS+
  • Mutation
  • SCN1A
  • SMEI
  • Sodium channel

ASJC Scopus subject areas

  • Neurology

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