Abstracts

Rationale: Mutations in ion channel genes disrupt the function of oligogenic macromolecular transmembrane channel complexes, and are known to contribute to pathophysiological networks in epilepsy. Personal profiles of gene variants, or channotype , typically harbor multiple mutations in known human epilepsy genes, and the pathogenic valence of any singular channel mutation depends on their electrogenetic contribution to the network. Here we explore combinations of gain and loss-of-function mutations in channel subunits in silico to identify those which predispose to hyperexcitability in hippocampal neurons and networks.Methods: Computational models of epilepsy-relevant CA1 and CA3 hippocampal neurons populated with ion channel complexes mimicking in vivo<