Abstracts

Rationale: Due to their extreme differences in response to many types of seizure-evoking stimuli, C57BL/6J (B6) and DBA/2J (D2) mice represent a genetic model with relevance to epilepsy. To confirm seizure susceptibility (SZS) QTLs on chromosome (chr) 15 that were identified previously using B6 and D2 mice, and to refine their genomic map position, we studied a set of three congenic strains in which overlapping segments of chr 15 from D2 were transferred onto the B6 background. Methods: We measured thresholds for generalized electroshock seizure (GEST) and maximal electroshock seizure (MEST) in congenic strains and B6-like littermates and also tested their responses to systemic injection of kainic acid (KA) and pentylenetetrazol (PTZ). Results: Results document that MEST is significantly lower in strains 15M and 15D, which harbor medial and distal (telomeric) segments of chr 15 (respectively) from D2, compared to strain 15P, which harbors the proximal (acromeric) segment of chr 15 from D2, and to control littermates. Congenic strains 15P and 15M exhibited greater KA SZS compared to strain 15D and B6-like controls. All congenic strains were similar to controls with regard to PTZ SZS. Conclusions: Taken together, results suggest there are multiple SZS QTLs on chr 15 and that two QTLs contain gene variants that affect MEST and KA SZS independently. The MEST QTL is refined to a 19 Mb region flanked by rs13482630 and D15Mit159. This interval contains 350 genes, 183 of which reside in areas that are not identical by descent between B6 and D2 and where the polymorphism rate is high. The KA QTL interval spans a 65 Mb region flanked by markers D15Mit13 and rs31271969. It harbors 83 genes in highly polymorphic areas; 310 genes in all. Complete dissection of these loci will lead to identification of genetic variants that influence SZS in mice and provide a better understanding of seizure biology.