title: Increased neuronal firing in computer simulations of sodium channel mutations that cause generalized epilepsy with febrile seizures plus.
abstract: Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial syndrome with a complex seizure phenotype. It is caused by mutations in one of 3 voltage-gated sodium channel subunit genes (SCN1B, SCN1A, and SCN2A) and the GABA(A) receptor gamma2 subunit gene (GBRG2). The biophysical characterization of 3 mutations (T875M, W1204R, and R1648H) in SCN1A, the gene encoding the CNS voltage-gated sodium channel alpha subunit Na(v)1.1, demonstrated a variety of functional effects. The T875M mutation enhanced slow inactivation, the W1204R mutation shifted the voltage dependency of activation and inactivation in the negative direction, and the R1648H mutation accelerated recovery from inactivation. To determine how these changes affect neuronal firing, we used the NEURON simulation software to design a computational model based on the experimentally determined properties of each GEFS+ mutant sodium channel and a delayed rectifier potassium channel. The model predicted that W1204R decreased the threshold, T875M increased the threshold, and R1648H did not affect the threshold for firing a single action potential. Despite the different effects on the threshold for firing a single action potential, all of the mutations resulted in an increased propensity to fire repetitive action potentials. In addition, each mutation was capable of driving repetitive firing in a mixed population of mutant and wild-type channels, consistent with the dominant nature of these mutations. These results suggest a common physiological mechanism for epileptogenesis resulting from sodium channel mutations that cause GEFS+.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California 92697-4025, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Spampanato
authors.forename: Ildiko
authors.initials: I
authors.lastname: Aradi
authors.forename: Ivan
authors.initials: I
authors.lastname: Soltesz
authors.forename: Alan L
authors.initials: AL
authors.lastname: Goldin
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000465:Algorithms; D000818:Animals; D003198:Computer Simulation; D004594:Electrophysiology; D004829:Epilepsy, Generalized / Q000503:physiopathology*; D005334:Fever / Q000150:complications* / Q000503:physiopathology*; D066298:In Vitro Techniques; D007700:Kinetics; D008959:Models, Neurological; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology; D012640:Seizures / Q000209:etiology* / Q000503:physiopathology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*; D012984:Software; D014982:Xenopus laevis
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D026941:Sodium Channel Blockers; D015222:Sodium Channels