Environmental Risk Factors for Multifactorial Epilepsy in EL Mice

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 x EL F, hybrids from ages 30-1 80 days.Results; Seizure induction was necessary in EL mice, as spontaneous clinical seizures were not observed. Handlinginduced 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 x ABP F, 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 x EL F, hybrids than in their reciprocal EL x ABP F, 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 stresdfear 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+nvironment interactions and in identifying susceptibility genes for multifactorial epilepsy.

Stimulus-Induced Behavior in F1 Hybrids of Seizure-Sensitive and Seizure-Resistant Gerbils

“…When a mild stimulus was used to elicit generalized seizures, however, the F1 hybrids from a DDY female x EL male pair were more susceptible at 90 to 150 d than those from an EL female x DDY male pair (Todorova et al , 1999). Our results do not indicate such a paternal effect, which suggests some difference in the mechanism underlying stimulus-induced seizure between these animal models.…”

“…It is also possible that the gene product mainly responsible varies with the amount or degree of activity of modulation in different individuals. Alternatively, several factors, each of which has a minor effect, might work together to induce seizures, as has been suggested for seizures in the EL mouse, a model animal of multifactorial idiopathic epilepsy (Rise et al , 1991;Todorova et al , 1999;Legare et al , 2000;Berkovic and Scheffer, 2001). In this case, summation of the contribution of individual factors might vary within each group.…”

The Ketogenic Diet Inhibits Epileptogenesis in EL Mice: A Genetic Model for Idiopathic Epilepsy

“…A new seizure testing procedure was developed that involved repetitive handling and simulated the situation normally associated with routine cage-changing, i.c., picking the mouse up by the tail for short intervals and moving it from a home cage to a new cage with fresh bedding (12). The test included two trials that were scparated by 30 minutes.…”

“…Seizure susceptibility in EL mice is age-dcpendent, with generalized seizures developing by 60 to 70 days of age and persisting throughout life. However, epileptogenesis in this animal model probably starts earlier because environmental stimulation at 30 days of age can influence generalized seizure onset ( 12). The seizures originate in or near the parietal lobe and then spread quickly (generalize) to the hippocampus and to other brain regions ( I 3).…”

Seizure logging: A new approach to synchronized cable-free EEG and video recordings of seizure activity in mice

“…Such cable-based systems hardly impose problems for studies of seizures that rely on electrical or chemical induction. However, in many epilepsy models, the most studied being the El mouse, seizures appear during complex stimulus situations such as daily handling procedures (Etholm and Heggelund, 2009;Kitami et al, 2004;Todorova et al, 1999). In such studies cable-based systems cause problems because one would try to mimic situations where seizures are normally seen.…”