To define the genetic contributions affecting individual differences in seizure threshold, a β carboline [methyl-β-carboline-3-carboxylate (β- CCM)]-induced model of generalized seizures was genetically dissected in mice. β-CCM is a GABA(A) receptor inverse agonist and convulsant. By measuring the latency to generalized seizures after β-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 ~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 β-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.
|Number of pages||8|
|Journal||Journal of Neuroscience|
|State||Published - May 15 1999|
- Individual differences
- Open field
- Quantitative trait locus (QTL)