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

• Published in: Neurobiology of disease 2009-07, Vol.35 (1), p.91-102
• Main Authors: Tang, Bin, Dutt, Karoni, Papale, Ligia, Rusconi, Raffaella, Shankar, Anupama, Hunter, Jessica, Tufik, Sergio, Yu, Frank H, Catterall, William A, Mantegazza, Massimo, Goldin, Alan L, Escayg, Andrew
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Arginine - genetics; Biophysical Phenomena; Cells, Cultured; Chromosomes, Artificial, Bacterial - physiology; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography - methods; Electromyography - methods; Epilepsy; Epilepsy, Generalized - chemically induced; Epilepsy, Generalized - complications; Epilepsy, Generalized - genetics; Epilepsy, Generalized - pathology; GEFS; Histidine - genetics; Kainic Acid; Membrane Potentials - drug effects; Membrane Potentials - genetics; Membrane Potentials - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Mutation - genetics; NAV1.1 Voltage-Gated Sodium Channel; Nerve Tissue Proteins - genetics; Neurology; Neurons - physiology; Patch-Clamp Techniques; RNA, Messenger - metabolism; SCN1A; Seizures, Febrile - chemically induced; Seizures, Febrile - complications; Seizures, Febrile - genetics; Seizures, Febrile - pathology; SMEI; Sodium channel; Sodium Channel Blockers - pharmacology; Sodium Channels - genetics; Tetrodotoxin - pharmacology
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2009.04.007

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.