GENETIC EPILEPSY MODEL DERIVED FROM COMMON INBRED MOUSE STRAINS

The recombinant inbred mouse strain, SWXL-4, exhibits tonic-clonic and generalized seizures similar to the commonest epilepsies in humans. I n SWXL-4 animals, seizures are observed following routine handling at about 80 days of age and may be induced as early as 55 days by rhythmi c gentle tossing. Seizures are accompanied by rapid, bilateral high fr equency spike cortical discharges and followed by a quiescent post-ict al phase. Immunohistochemistry of the immediate early gene products c- Fos and c-Jun revealed abnormal activation within cortical and limbic structures. The seizure phenotype of SWXL-4 can be explained and repli cated fully by the inheritance of susceptibility alleles from its prog enitor strains, SWR/J and C57L/J. outcrosses of SWXL-4 with most other common inbred strains result in F-1 hybrids that have seizures at lea st as frequently as SWXL-4 itself. Quantitative trait locus mapping re veals a seizure frequency determinant, Szf1, near the pink-eyed diluti on locus on chromosome 7, accounting for up to 32% of the genetic vari ance in an F-2 intercross between SWXL-4 and the linkage testing strai n ABP/Le. These studies demonstrate that common strains of mice such a s SWR and C57L contain latent epilepsy susceptibility alleles. Althoug h the inheritance of susceptibility may be complex, these results impl y that a number of potentially important and practical, noninvasive mo dels for this disorder can be constructed and studied in crosses betwe en common mouse strains.