Mapping loci for pentylenetetrazol-induced seizure susceptibility in mice

Abstract

DBA/2J (D2) and C57BL/6J (B6) mice exhibit differential sensitivity to seizures induced by various chemical and physical methods, with D2 mice being relatively sensitive and B6 mice relatively resistant. We conducted studies in mature D2, B6, F1, and F2 intercross mice to investigate behavioral seizure responses to pentylenetetrazol (PTZ) and to map the location of genes that influence this trait. Mice were injected with PTZ and observed for 45 min. Seizure parameters included latencies to focal clonus, generalized clonus, and maximal seizure. Latencies were used to calculate a seizure score that was used for quantitative mapping. F2 mice (n = 511) exhibited a wide range of latencies with two-thirds of the group expressing maximal seizure. Complementary statistical analyses identified loci on proximal (near D1Mit11) and distal chromosome 1 (near D1Mit17) as having the strongest and most significant effects in this model. Another locus of significant effect was detected on chromosome 5 (near D5Mit398). Suggestive evidence for additional PTZ seizure-related loci was detected on chromosomes 3, 4, and 6. Of the seizure-related loci identified in this study, those on chromosomes 1 (distal), 4, and 5 map close to loci previously identified in a similar F2 population tested with kainic acid. Results document that the complex genetic influences controlling seizure response in B6 and D2 mice are partially independent of the nature of the chemoconvulsant stimulus with a locus on distal chromosome 1 being of fundamental importance.

Fig. 1.

Distribution of seizure scores among F2 mice. Scores were calculated as described in Materials and Methods. Other population summary data are given in Tables 2 and 3.

Fig. 2.

Genetic maps indicating interval LOD scores for linkage to loci controlling PTZ-induced seizure susceptibility in F2 mice. LOD scores were determined with Mapmaker/QTL using seizure score as the trait measure. Scores represent the results of model-independent analyses. A, Chromosome 1 [for comparison, this plot also contains data on kainic acid seizure susceptibility redrawn fromFerraro et al., (1997)]; B, chromosome 4;C, chromosome 5.