10 - Computer Simulations of Sodium Channel Mutations that Cause Generalized Epilepsy with Febrile Seizures Plus

Abstract

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial syndrome encompassing an array of clinical seizure phenotypes. Identification of a GEFS+ family requires diagnosis through multiple generations of febrile seizures that persist beyond six years of age. GEFS+ is an autosomal dominant familial syndrome with a complex seizure phenotype. It is caused by mutations in one of three voltage gated sodium channel subunit genes (SCN1B, SCN1A and SCN2A) or the GABAA receptor γ2 or δ subunit genes (GBRG2 and GABRD). The biophysical characterization of four mutations (T875M, W1204R, R1648H and D1866Y) in SCN1A, the gene encoding the central nervous system (CNS) voltage-gated sodium channel subunit Nav1.1, demonstrated a variety of functional channel defects. To determine how these changes in sodium channel function might affect neuronal firing, the NEURON simulation software was used to design a computational spiking neuron model based on the experimentally determined properties of each GEFS+ mutant sodium channel. Despite the different effects on channel function, each mutation altered action potential generation in a manner that was consistent with hyperexcitability. The computational model was utilized to demonstrate further multiple mechanisms by which one mutation (D1866Y) might enhance neuronal excitability through its supralinear dominance over wild-type function in a mixed population.