Mapping quantitative trait loci for seizure response to a GABAA receptor inverse agonist in mice

Abstract

To define the genetic contributions affecting individual differences in seizure threshold, a beta carboline [methyl-beta-carboline-3-carboxylate (beta-CCM)]-induced model of generalized seizures was genetically dissected in mice. beta-CCM is a GABAA receptor inverse agonist and convulsant. By measuring the latency to generalized seizures after beta-CCM administration to A/J and C57BL6/J mice and their progeny, we estimated a heritability of 0.28 +/- 0.10. A genome wide screen in an F2 population of these parental strains (n = 273) mapped quantitative trait loci (QTLs) on proximal chromosome 7 [logarithm of the likelihood for linkage (LOD) = 3.71] and distal chromosome 10 (LOD = 4.29) for seizure susceptibility, explaining approximately 22 and 25%, respectively, of the genetic variance for this seizure trait. The best fitting logistic regression model suggests that the A/J allele at each locus increases the likelihood of seizures approximately threefold. In a subsequent backcross population (n = 223), we mapped QTLs on distal chromosome 4 (LOD = 2.88) and confirmed the distal chromosome 10 QTLs (LOD = 4.36). In the backcross, the C57BL/6J allele of the chromosome 10 QTL decreases the risk of seizures approximately twofold. These QTLs may ultimately lead to the identification of genes influencing individual differences in seizure threshold in mice and the discovery of novel anticonvulsant agents. The colocalization on distal chromosome 10 of a beta-CCM susceptibility QTL and a QTL for open field ambulation and vertical movement suggests the existence of a single, pleiotropic locus, which we have named Exq1.

Fig. 1.

QTL likelihood plots on the F2 population for (A) chromosome 7 and (B) chromosome 10 and on the N2(B6AF1xA/J) backcross population for (C) chromosome 4 and (D) chromosome 10 from Mapmaker/QTL analyses. Logarithm of the likelihood ratio for linkage (LOD) score is plotted against map distance in centimeters for the traits of seizure latency, rank-ordered (●), average of three trials of light↔dark transitions (AvgLD, ▪), initial O-F total distance ambulated (TDe1, ▴), habituated O-F total distance ambulated (TDe3, [tridf]), and O-F vertical movements (VM15, ♦). For the F2 hybrids with 2 df, the published threshold values for suggestive and significant linkage are LOD = 2.8 and LOD = 4.3, respectively, whereas the empirically derived threshold values from 10,000 permutations for the ranked latency to seizure gave values of 2.3 and 3.7, respectively. For the N2(B6AF1xA/J) cross with 1 df, the published threshold values for suggestive and significant linkage are LOD = 1.9 and LOD= 3.3, respectively, whereas the empirically derived values for the ranked latency to seizure gave values of 1.4 and 2.7. These QTL plots used the genotyping of 11 and 12 DNA markers for chromosome 7 and 10 in the F2 hybrids, whereas the backcross offspring used the genotyping of 7 and 10 DNA markers for chromosomes 4 and 10, respectively.