Experimental models of multifactorial epilepsies: the EL mouse and mice susceptible to audiogenic seizures.

This chapter reviews two well-characterized mouse epilepsy models with a multifactorial etiology, the epileptic EL mouse and mice susceptible to audiogenic seizures (AGS). Multifactorial disorders are quantitative traits where the action of more than one gene together with environmental factors contributes to the disease phenotype. The EL (epilepsy) mouse has been studied extensively as a genetic model for idiopathic complex partial seizures in humans. EL seizures are associated with an intense hippocampal gliosis in the absence of obvious neuronal loss and an elevated calcium-dependent release of aspartate that is present both before and after seizure onset. The inheritance of epilepsy is complex and several seizure frequency quantitative trait loci (QTL) have been mapped. Much of this genetic complexity may arise from the influence of environmental factors, including the seizure testing procedure, seizure history, and age. AGS, which are violent sound-induced convulsions, are considered a genetic model for generalized brainstem or reflex epilepsies. AGS susceptibility can arise as an inherited trait in some mouse strains or can be induced in genetically resistant strains from environmental factors (e.g., prior acoustic stimulation). AGS susceptibility and long-term potentiation (LTP) may also share common mechanisms. Several Asp genes have been mapped that influence AGS susceptibility. The expression of one of these can be modified by genomic imprinting and another has been identified as the X-linked 5-HT2e serotonin receptor. The genetic dissection of convulsive behavior in EL and AGS susceptible mice could help identify candidate genes for human multifactorial epilepsies.

Environmental influences on epilepsy gene mapping in EL mice.

The epileptic EL mouse has been studied extensively as a genetic model for idiopathic complex partial seizures in humans. The seizures in EL mice occur during routine handling at approximately 90 days of age, but can be induced at younger ages (50 days) by repeated rhythmic vestibular stimulation, e.g., tossing. Six seizure frequency quantitative trait loci (QTLs), El1-El6, were previously mapped in crosses between EL and non-epileptic strains using mechanical tossing procedures beginning at 30 days of age. The presence of these seizure frequency QTLs depended upon genetic background and the type of cross. Here we confirm Chromosome 2 and 9 QTLs in a backcross to the seizure-resistant ABP/LeJ strain with mice tested beginning at 200 days of age. However, the mapping of epilepsy genes was influenced by the seizure testing procedure, i.e., repeated tossing. The maximum Z-score for El1 (Chromosome 9) was 3.7 after 6 tests, but decreased to 2.4 after 15 tests. In contrast, the maximum Z-score for El2 (Chromosome 2) was 2.0 after 6 tests, but increased to 3.9 after 15 tests. In addition to nonallelic interactions (epistasis), our findings indicate that the genetic complexity of tossing-induced seizure susceptibility in EL mice also arises from genotype-environmental interactions involving the seizure test, seizure history, and age.