Analysis of Candidate Genes for Seizure Susceptibility in Epileptogenesis

摘要

The occurrence of recurrent spontaneous seizures is the hallmark of epilepsy. The key to understanding how a normal brain can develop epilepsy through a process known as epileptogenesis is identifying susceptibility factors. Previously, various strains of inbred mice from the hybrid mouse diversity panel were subjected to multiple seizures via the repeated flurothyl model (RFM) for epileptogenesis. The results demonstrated differences in kindling among the inbred strains; specifically two main trends in the generalized seizure threshold (GST) data were kindling-sensitive and kindling-resistant strains. In addition, genome wide association studies done from these mice demonstrated a quantitative trait locus (QTL) on the distal end of chromosome 4 that is associated with the differences related to repeated seizures. Given the emphasis on genetic differences underlying adaptations to seizures, mRNA expression of the four genes, Camta1, Per3, Vamp3, and Park7, that are within 1 megabase (MB) of the QTL were analyzed in C57BL/6J (B6) and DBA/2J (D2) mice, as these strains represent the two distinct seizure outcomes. The results demonstrate a differential expression of all four genes in different brain regions between the strains before and after repeated seizures. The most significant differences were in Per3 expression after repeated seizures, in both the cortex and hippocampus, but there were also significant differences in Vamp3 and Park7 in the hippocampus and cerebellum, respectively. The changes observed in expression of these genes after multiple seizures are key to identifying the best epileptogenesis susceptibility factor candidate for further research.