Abstracts

Rationale: The repeated flurothyl model (RFM) uses the chemoconvulsant flurothyl to induce 1 seizure per day for 8 consecutive days in mice. In C57BL/6J (B6) mice, this repeated daily exposure results in the expression of myoclonic jerks, clonic seizures, and a decrease in generalized seizure threshold (GST) across the 8 trials that is permanent by trial 5. Mice are again exposed to flurothyl (retest), 30 days after the 8th seizure trial. Upon retest, B6 mice maintain their lowered GST and have a change in behavioral seizure phenotype from a clonic-forebrain seizure to a clonic-forebrain seizure which rapidly progresses into a tonic-brainstem seizure. In the RFM, DBA/2J (D2) mice have a lower initial GST, do not display decreases in GST across the 8 trials, and do not have a change in seizure phenotype upon retest. Recombinant inbred (RI) lines are inbred mice that are used to identify QTLs for a variety of behaviors. BXD RI mice are derived from B6 and D2 parental strains. Using a variety of seizure-inducing stimuli, QTLs have been reported for seizure susceptibility. Here, we utilize available BXD lines and test these lines in the RFM to identify QTLs that control flurothyl-seizure susceptibility, the decreases in GST across the 8 trials, the permanent decrease in GST, and the change in seizure phenotype. Methods: Twenty-eight of the available Taylor BXD RI lines were tested in the RFM. Briefly, mice received 1 flurothyl-induced seizure per day for 8 consecutive trials. Following the 8th trial, animals remained in their home cages for 28-30 days with no exposure to flurothyl. Then, animals were retested with flurothyl. Results: None of the seizure traits measured (myoclonic jerk (MJ) threshold, MJ #, initial GST, the change in GST across the 8 trials, or the change in seizure phenotype) show evidence of linkage to the known distal chromosome 1 seizure locus (Kcnj10) or the chromosome 4 seizure locus (Mpdz), indicating that we are likely to identify novel QTLs. In fact, we have 2 to 3 distinct and suggestive QTL peaks per trait for MJ threshold, MJ #, and the change in GST over trials. For initial GST, we have a significant interaction between chromosomes 10 and 15. Finally, the change in seizure phenotype has a single significant QTL on chromosome 7. Conclusions: Our data suggest that differences in flurothyl seizure characteristics between BXD strains can be mapped to distinct QTLs. Data on the change in seizure phenotype in the BXD RI lines indicates a dissociation of flurothyl seizure traits in these lines. The dissociation between the change in GST across 8 seizure trials phenotype and the change in seizure phenotype are suggestive of different reorganizational processes that may account for these differences. Overall, data from the analysis of the BXD RI strains strongly supports the hypothesis that the differences in seizure characteristics in the RFM between different RI lines of mice are due to differences in genetic background. The RFM, in combination with RI line analysis, serves as an excellent system by which to begin to identify regions in the mouse genome responsible for these traits.