Environmental Risk Factors for Multifactorial Epilepsy in EL Mice

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Abstract
Summary: Purpose: The epileptic EL mouse has been studied extensively as a model of multifactorial epilepsy. Although EL mice have a seizure occasionally during routine handling associated with cage changing, most studies have used vigorous tossing or shaking procedures for seizure induction. A new seizure testing procedure was developed that involved gentle handling and simulated situations associated with emotional stress in rodents. This new testing procedure was used to identify and characterize several environmental risk factors that influence seizure predisposition in EL mice. Methods: Ten adult EL mice were monitored for 7 days under 24‐h light/dark video surveillance to assess the frequency of spontaneous seizures. The development of handling‐induced seizures also was studied in EL mice, in nonepileptic ABP and DDY mice, and in reciprocal ABP × EL F1 hybrids from ages 30–180 days. Results: Seizure induction was necessary in EL mice, as spontaneous clinical seizures were not observed. Handling‐induced seizure susceptibility was strongly age and gender dependent in naive EL mice (not previously handled) and peaked ‐90 days, with males significantly more susceptible than females. No seizures were induced by handling in the nonepileptic mouse strains (ABP and DDY) over the testing period. Handling and seizures at young ages in EL and EL × ABP F1 hybrid mice significantly enhanced their seizure susceptibility when they were tested again 1 month later. A significant “Gowers effect” was seen also in EL mice. Furthermore, susceptibility was higher in ABP × EL F1 hybrids than in their reciprocal EL × ABP F1 hybrids at 90–150 days. Conclusions: Seizure susceptibility in EL mice was significantly influenced by a number of environmental factors including age, gender, maternal/paternal effects, prior handling, and seizure history. The emotional stress/fear response is the likely trigger for seizure induction in EL mice. An early life experience stress‐diathesis model, similar to that proposed for major depression in humans, was applicable to the development of seizure susceptibility in EL mice. The new seizure test will be useful for defining gene‐environment interactions and in identifying susceptibility genes for multifactorial epilepsy.