Mapping quantitative trait loci for seizure response to a GABA(A) receptorinverse agonist in mice

To define the genetic contributions affecting individual differences in sei zure threshold, a beta carboline [methyl-beta-carboline-3-carboxylate (beta -CCM)]-induced model of generalized seizures was genetically dissected in m ice. beta-CCM is a GABA(A) receptor inverse agonist and convulsant. By meas uring the latency to generalized seizures after beta-CCM administration to A/J and C57BL6/J mice and their progeny, we estimated a heritability of 0.2 8 +/- 0.10. A genome wide screen in an F2 population of these parental stra ins (n = 273) mapped quantitative trait loci (QTLs) on proximal chromosome 7 [logarithm of the likelihood for linkage (LOD) = 3.71] and distal chromos ome 10 (LOD = 4.29) for seizure susceptibility, explaining similar to 22 an d 25%, respectively, of the genetic variance for this seizure trait. The be st fitting logistic regression model suggests that the A/J allele at each l ocus increases the likelihood of seizures approximately threefold. In a sub sequent backcross population (n = 223), we mapped QTLs on distal chromosome 4 (LOD = 2.88) and confirmed the distal chromosome 10 QTLs (LOD = 4.36). I n 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 t hreshold in mice and the discovery of novel anticonvulsant agents. The colo calization on distal chromosome 10 of a beta-CCM susceptibility QTL and a Q TL for open field ambulation and vertical movement suggests the existence o f a single. pleiotropic locus, which we have named Exq1.