Abstracts

Inbred mouse strains are valuable to identify genes contributing to complex genetic diseases such as epilepsy. Chromosome substitution strains (CSS) are strains in which a single chromosome from one inbred strain (donor) has been transferred onto a second strain (host) by repeated backcrossing. A panel of CSS in which each chromosome is represented may be used to identify quantitative trait loci (QTLs) that contribute to a phenotype. Pilocarpine hydrochloride is a muscarinic cholinergic agonist that causes limbic seizures in mice, modeling human temporal lobe epilepsy. QTLs for susceptibility to pilocarpine-induced seizures have not been reported. C57BL/6J (B6) mice have been shown to be resistant to seizures; the A/J strain has been less studied, but appears more susceptible to seizures. Here, we report QTLs identified using a B6 (host) X A/J (donor) CSS panel to localize genes involved in susceptibility to pilocarpine-induced seizures., 340 adult male mice--at least 10 of each CSS, 50 B6, and 39 A/J--were tested for susceptibility to pilocarpine-induced seizures between 10 and 12 weeks of age. Mice were pretreated with atropine (5 mg/kg), followed in 30 minutes by pilocarpine (250 mg/kg), then continuously observed for 3 hours. Using a seizure staging system adapted from established (Racine) rodent seizure scales, highest stage reached, latency to each stage, and latency between stages were recorded for all mice. Significance of results in the CSS panel screen was determined by nonparametric comparison of mean highest stage reached (Mann-Whitney), and cox proportional hazard regression was used to generate hazard ratios and p-values for latency variables., B6 mice were more resistant to seizures and were slower to reach each stage compared to A/J mice (p[lt].01). The CSS for chromosomes 10 and 18 progressed to the most severe seizure stages, diverging dramatically from the B6 seizure-resistant phenotype (p[lt].01). Latency to all seizure stages and between stages was also significantly shorter for CH10 and CH18 mice, with hazard rates as high as 25 times that of B6 mice., Results of CSS mapping suggest the presence of seizure susceptibility loci on mouse chromosomes 10 and 18. This approach can provide a framework for identifying potentially novel homologous candidate genes for human temporal lobe epilepsy., (Supported by NINDS K23 NS02211, K02 NS050429, R01 NS36319, R0141490.)