Quantitative genetic study of maximal electroshock seizure threshold in mice: Evidence for a major seizure susceptibility locus on distal chromosome 1

We conducted a quantitative trait locus (QTL) mapping study to dissect the multifactorial nature of maximal electroshock seizure threshold (MEST) in C 57BL/6 (B6) and DBA/2 (D2) mice. MEST determination involved a standard par adigm in which 8- to 12-week-old mice received one shock per day with a dai ly incremental increase in electrical current until a maximal seizure (toni c hindlimb extension) was induced. Mean MEST values in parental strains wer e separated by over five standard deviation units, with D2 mice showing low er values than B6 mice. The distribution of MEST values in B6 x D2 F2 inter crossed mice spanned the entire phenotypic range defined by parental strain s. Statistical mapping yielded significant evidence for QTLs on chromosomes 1, 2, 5, and 15, which together explained over 60% of the phenotypic varia nce in the model. The chromosome 1 QTL represents a locus of major effect, accounting for about one-third of the genetic variance. Experiments involvi ng a congenic strain (B6.D2-Mtv7(a)/Ty) enabled more precise mapping of the chromosome 1 QTL and indicate that it lies in the genetic interval between markers D1Mit145 and D1Mit17. These results support the hypothesis that th e distal portion of chromosome 1 harbors a gene(s) that has a fundamental r ole in regulating seizure susceptibility.