SOUND-INDUCED SEIZURES IN SEROTONIN 5-HT2C RECEPTOR MUTANT MICE

The epilepsies are a heterogeneous collection of seizure disorders wit h a lifetime expectancy risk rate of 2-4%(1). A convergence of evidenc e indicates that heritable factors contribute significantly to seizure susceptibility(2,3). Genetically epilepsy-prone rodent strains have b een frequently used to examine the effect of genetic factors on seizur e susceptibility. The most extensively studied of these have been stra ins that are susceptible to sound-induced convulsions (audiogenic seiz ures, or AGSs). Early observations of the ACS phenomenon were made in the laboratory of Dr. Ivan Pavlov; in the course of appetite-condition ing experiments in mice, the loud bell used to signal food presentatio n unexpectedly produced seizures in some animals(4). In 1947, DBA/2 (D 2) mice were found to exhibit a genetic susceptibility to AGSs stimula ted by a doorbell mounted in an iron tub(5). Since this discovery, AGS s have been among the most intensively studied phenotypes in behaviour al genetics(6,7). Although several genetic loci confer susceptibility to AGSs, the corresponding genes have not been cloned. We report that null mutant mice lacking serotonin 5-HT2C receptors are extremely susc eptible to AGSs. The onset of susceptibility is between two and three months of age, with complete penetrance in adult animals. ACS-induced immediate early gene expression indicates that AGSs are subcortical ph enomena in auditory circuits. This AGS syndrome is the first produced by a known genetic defect; it provides a robust model for the examinat ion of serotoninergic mechanisms in epilepsy.