Genetic heterogeneity for the development of audiogenic seizures in mice

Abstract

Susceptibility to audiogenic seizures (AS) in mice is age dependent. In the prototype DBA/2 (D2) strain, AS susceptibility is greatest around 21 days of age (juvenile-onset), but then gradually subsides. By the time D2 mice reach adulthood (60–80 days) they become completely resistant to AS. Mice of the C5BL/6 (B6) strain are resistant to AS at all ages. Even though the D2 and B6 strains are AS-resistant at adult ages, several B6 × D2 (BXD) recombinant inbred (RI) strains are highly AS-susceptible as adults. Previous studies showed that AS susceptibility in 21-day-old mice was strongly influenced by a major gene, Ias, closely linked to the Ah locus. It appears, however, that Ias does not influence AS susceptibility in adult mice since no association was found between the Ah locus and AS susceptibility in adult BXD RI strains. Furthermore, the developmental profile of AS susceptibility in one RI strain, BXD-15, was biphasic. The incidence of clonic-tonic seizures in these mice at 21, 42 and 60–80 days of age was 82.2%, 14.8%, and 66.6%, respectively. The inheritance of AS susceptibility in the F 1 hybrids from crosses between the B6, D2, and BXD-15 strains was also different at young and adult ages. The incidence of clonic-tonic seizures in the B6BXD-15F 1 hybrids went from 0% at 21 days of age to 24% at 60–80 days; whereas the incidence of clonic-tonic seizures in the D2BXD-15F 1 hybrids went from 100% at 21 days to 0% at 60–80 days. Subtle differences were also observed between young and adult mice for the latency period (in seconds) to seizure onset, for the type of seizures, and for the incidence of seizures in males and females. Taken together, these findings suggest that the genetic mechanism responsible for juvenile-onset AS susceptibility is different from that responsible for adult-onset AS susceptibility in BXD-15 mice. The implications of these findings to the study of certain human idiopathic epilepsies are mentioned.