Abstracts

Rationale: Although C57BLKS/J (BKS) and C57BL/10SnJ (B10S) mice share a large proportion of their genomes identical by descent, they exhibit a number of phenotypic differences that are due at least in part to the influence of segments of the genome inherited from different ancestors. Previously, we have shown that B10S mice are resistant to experimental seizures, exhibiting a relatively high electrical seizure threshold. In contrast, BKS mice exhibit a relatively low seizure threshold. In the present study, we have confirmed the significant difference in maximal electroshock seizure threshold (MEST) between BKS and B10S mice and have used an F2 intercross population to map quantitative trait loci (QTL) that contribute to this effect. Methods: BKS, B10S, BKS x B10S F1 and BKS x B10S F2 (F1 intercross) mice were tested for MEST at 8-9 weeks of age. F2 results showed that in this cross MEST is a continuously distributed trait determined by polygenic inheritance. Similar numbers of male and female mice from each tail of the F2 distribution (n = 45 lowest MEST and n = 49 highest MEST) were genotyped using microarray technology. A sequential series of statistical analyses was used to map QTLs including single point, multi-point and multi-locus methods. Results: MEST was observed to be correlated significantly with gender (P < 0.04) and body weight (P < 0.002) and thus QTL mapping was conditioned on these two factors. Four QTLs reached genome-wide levels of significance based upon interval mapping using logistic regression combined with permutation analysis: Chr 3 (~67 cM), Chr 4 (~49 cM), Chr 6 (~66 cM) and Chr 8 (~31 cM). Together the four QTLs explained about 45% of the total phenotypic variance in the model. The locus of greatest effect was on Chr 6 (P < 0.0001). There was no epistatic interaction detected between any of the loci. Conclusions: We have mapped QTLs for the difference in MEST between BKS and B10S mice. The lack of overlap between MEST QTLs mapped in this study and those mapped in previous studies involving C57BL/6J and DBA/2J mice, strains that are closely related to those used in the present study, support the hypothesis that BKS and B10S mice represent a new model for investigating genetic susceptibility to seizures.