This research proposal examines epilepsy-associated mutations in the human voltage-gated sodium channel gene SCN1A with the goal of elucidating novel mechanisms of abnormal neuronal excitability. Voltage-gated sodium channels are responsible for the initiation, maintenance, and propagation of action potentials in excitable membranes. Recently, several inherited epilepsies have been linked to mutations in various sodium channel genes (SCN1A, SCN1B, and SCN2A). However, functional studies of these mutants have revealed a complex relationship between biophysical defect and epilepsy phenotype. This proposal aims to: 1) Characterize the single-channel biophysical properties of the SCN1A mutant R1648C (causing severe myoclonic epilepsy of infancy (SMEI)) to investigate alterations in channel gating that may induce abnormal neuronal excitability; and 2) Determine the effect of the SCN1A mutants R1648H and R1648C on neuronal excitability using empirical-based computational modeling of neuronal action potentials. These experiments will help elucidate the molecular basis of epilepsy, thereby advancing our understanding of epileptogenesis in general, and providing information useful for the design of new therapies. Relevance: Sodium channels are proteins in nerve cell membranes involved in generating electrical activity in the brain. Genetic defects in sodium channels can result in several types of epilepsy ranging in severity from mild to malignant. This research examines how naturally identified mutations disturb sodium channel function to cause epilepsy. ? ? ?
| Henninger, Nils; Bouley, James; Sikoglu, Elif M et al. (2016) Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1. Brain 139:1094-105 |
| Kahlig, Kristopher M; Rhodes, Thomas H; Pusch, Michael et al. (2008) Divergent sodium channel defects in familial hemiplegic migraine. Proc Natl Acad Sci U S A 105:9799-804 |
