title: A BAC transgenic mouse model reveals neuron subtype-specific effects of a Generalized Epilepsy with Febrile Seizures Plus (GEFS+) mutation.
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.
authors.affiliation: Department of Human Genetics, Emory University, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Tang
authors.forename: Karoni
authors.initials: K
authors.lastname: Dutt
authors.forename: Ligia
authors.initials: L
authors.lastname: Papale
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rusconi
authors.forename: Anupama
authors.initials: A
authors.lastname: Shankar
authors.forename: Jessica
authors.initials: J
authors.lastname: Hunter
authors.forename: Sergio
authors.initials: S
authors.lastname: Tufik
authors.forename: Frank H
authors.initials: FH
authors.lastname: Yu
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
authors.forename: Massimo
authors.initials: M
authors.lastname: Mantegazza
authors.forename: Alan L
authors.initials: AL
authors.lastname: Goldin
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000235:genetics; D055592:Biophysical Phenomena; D002478:Cells, Cultured; D022202:Chromosomes, Artificial, Bacterial / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D004829:Epilepsy, Generalized / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000473:pathology; D006639:Histidine / Q000235:genetics; D007608:Kainic Acid; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D003294:Seizures, Febrile / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000473:pathology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D006639:Histidine; D001120:Arginine; D007608:Kainic Acid