Sound-induced seizures in serotonin 5-HT2C receptor mutant mice

The epilepsies are a heterogeneous collection of seizure disorders with a lifetime expectancy risk rate of 2-4%(1). A convergence of evidence indicates that heritable factors contribute significantly to seizure susceptibility(2,3). Genetically epilepsy-prone rodent strains have been frequently used to examine the effect of genetic factors on seizure susceptibility. The most extensively studied of these have been strains that are susceptible to sound-induced convulsions (audiogenic seizures, or AGSs). Early observations of the ACS phenomenon were made in the laboratory of Dr. Ivan Pavlov; in the course of appetite-conditioning experiments in mice, the loud bell used to signal food presentation unexpectedly produced seizures in some animals(4). In 1947, DBA/2 (D2) mice were found to exhibit a genetic susceptibility to AGSs stimulated by a doorbell mounted in an iron tub(5). Since this discovery, AGSs have been among the most intensively studied phenotypes in behavioural 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 susceptible 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 phenomena in auditory circuits. This AGS syndrome is the first produced by a known genetic defect; it provides a robust model for the examination of serotoninergic mechanisms in epilepsy.