NEW SEIZURE FREQUENCY QTL AND THE COMPLEX GENETICS OF EPILEPSY IN EL MICE

EL/Suz (EL) mice experience recurrent seizures that are similar to com mon partial complex epilepsy in humans. In the mice, seizures occur na turally at 90-100 days of age, but can be induced in younger mice and analyzed as a semi-quantitative trait after gentle rhythmic stimulatio n, A previous genetic mapping study of EL backcrosses to the strains A BP/LeJ or DBA/2J showed two quantitative trait loci (QTL) with large e ffects on seizure frequency (El1, Chr 9; El2, Chr 2) and implied the e xistence of other QTL with lesser effects. To further the understandin g of EL-derived seizure alleles, we examined intercross progeny of EL and the strains ABP/LeJ and DDY/Jcl, and also a backcross of (EL x DDY ) F-1 hybrids to DDY. A new large-effect seizure frequency QTL was fou nd (El5, Chr 14), a more minor QTL confirmed (El3, Chr 10), and two ad ditional QTL proposed (El4, Chr 9; El6, Chr 11). The serotonin recepto r gene, Htr2a, maps near and is a candidate for El5, and linkages of o ther serotonin receptor genes to seizure frequency QTL are noted. In a ddition, a strong gender effect was revealed, and epistasis was found between Ctr 9 and Chr 14 markers. Despite this progress, however, our results revealed a more complex determinism of epilepsy in EL mice tha n previously described. In particular, no single E1 locus or pair was essential for frequent seizures, as QTL with large effects, such as El 5, El2. and El1, were highly dependent on genetic context. Our studies highlight the importance of gene interaction in some complex mammalia n traits defined by natural variation.