This proposal describes a rational system for the identification of genes that control seizure susceptibility in mice using a combination of quantitative trait locus (QTL) mapping and bioinformatic approaches. The proposed project builds on results of an ongoing K02-funded study in our laboratory in which we used B6 (host) X A/J (donor) chromosome substitution strains (B6.A CSS) to identify QTLs on five chromosomes that confer increased susceptibility to pilocarpine-induced limbic seizures, a rodent model of human temporal lobe epilepsy. We will use breeding and mapping strategies--including the creation of F2 populations and interval-specific congenics--in combination with bioinformatics techniques to fine map seizure susceptibility QTLs and identify candidate genes (QTGs). These QTGs can later be tested in human populations ascertained by the PI (Winawer) under separate K02 funding, or examined in experimental functional systems. We will apply similar strategies to map susceptibility QTLs for Electroconvulsive Threshold (ECT), to identify both model-specific and broadly-acting (generalized hyperexcitability) QTLs and QTGs. The combination of experimental and bioinformatics strategies is extremely powerful for identifying epilepsy candidate genes. This approach is made possible by the availability of databases derived from published literature, strain-specific sequence data, estimates of the density of inter-strain single nucleotide polymorphisms (SNPs) across the genome, and strain and region-specific expression databases.
Epilepsy, defined as recurrent seizures occurring without acute provocation, affects approximately 50 million people worldwide at any given time. There is substantial evidence for a genetic contribution to human epilepsy, but most epilepsy remains unexplained by genes discovered to date. Our proposal aims to identify genes associated with increased susceptibility to seizures. These genes can be examined in human populations as well as be investigated with functional experimental models. Discovery of susceptibility genes can provide insight into epilepsy pathophysiology and transform therapeutic strategies.
