A locus on mouse Ch10 influences susceptibility to limbic seizure severity: fine mapping andin silicocandidate gene analysis

Abstract

Identification of genes contributing to mouse seizure susceptibility can reveal novel genes or pathways that provide insight into human epilepsy. Using mouse chromosome substitution strains and interval-specific congenic strains (ISCS), we previously identified an interval conferring pilocarpine-induced limbic seizure susceptibility on distal mouse chromosome 10 (Ch10). We narrowed the region by generating subcongenics with smaller A/J Ch10 segments on a C57BL/6J (B6) background and tested them with pilocarpine. We also tested pilocarpine-susceptible congenics for 6-Hz ECT (electroconvulsive threshold), another model of limbic seizure susceptibility, to determine whether the susceptibility locus might have a broad effect on neuronal hyperexcitability across more than one mode of limbic seizure induction. The ISCS Line 1, which contained the distal 2.7 Mb segment from A/J (starting at rs29382217), was more susceptible to both pilocarpine and ECT. Line 2, which was a subcongenic of Line 1 (starting at rs13480828), was not susceptible, thus defining a 1.0 Mb critical region that was unique to Line 1. Bioinformatic approaches identified 45 human orthologs within the unique Line 1 susceptibility region, the majority syntenic to human Ch12. Applying an epilepsy network analysis of known and suspected excitability genes and examination of interstrain genomic and brain expression differences revealed novel candidates within the region. These include Stat2, which plays a role in hippocampal GABA receptor expression after status epilepticus, and novel candidates Pan2, Cdk2, Gls2 and Cs, which are involved in neural cell differentiation, cellular remodeling and embryonic development. Our strategy may facilitate discovery of novel human epilepsy genes.