Abstracts

We are conducting a genetic mapping study in mice to identify loci that represent genes whose sequence variation mediates differences in responsiveness to the anticonvulsant effects of VPA. Ultimately, identification of such genes and their variation will lead to focused hypotheses regarding the pharmacogenetics of VPA in human epilepsy patients. A panel of eight common inbred strains of mice was screened for baseline seizure sensitivity by measuring maximal electroshock seizure thresholds (MEST). Strain-specific effects of VPA were characterized by dose response experiments (100-500 mg/kg, i.p.) in which the percentage increase of MEST over bsaeline was determined. BALB/cJ and 129X1/SvJ were chosen to generate an F2 intercross population (n = about 600) for genetic mapping because they have equivalent baseline MESTs but distinctive responses to VPA: BALB/cJ is relatively resistant and 129X1/SvJ is relatively sensitive to the ability of VPA to increase MEST. The [quot]broad sense[quot] heritability of this effect is 0.7. F2 mice are injected with saline or VPA (200 mg/kg, i.p.) prior to MEST trials. Genome scans are underway in these two groups of mice utilizing standard microsatellite DNA markers at a resolution of approximately 15 cM With a first pass genome scan approximately 75% complete, single point contingency analysis (Mapmaker QTX) has revealed a number of putative QTLs. Suggestive (less than 0.05) or significant (less than 0.0001) P-values were obtained for markers on chromosomes 1 (D1Mit64, D1Mit365), 4 (D4Mit251, D4Mit42) , 6 (D6Mit123), 8 (D8Mit46), 9 (D9Mit311, D9Mit151), 15 (D15Mit13, D15Mit107), 18 (D18Mit186) and X (DXMit172) in the F2 cross pretreated with VPA. Putative QTLs on chromosomes 6 and 8 overlap with loci detected in the F2 cross pretreated with saline suggesting that they are seizure sensitivity QTLs and not specific for VPA response. VPA responsiveness in BALB/cJ and 129X1/SvJ mice is a complex trait that may be dissected using standard QTL mapping strategies. Preliminary data showing that these strains are also differentially sensitive to the anticonvulsant effects of phenytoin suggest the possibility that in mice, some genetic variation may influence responsiveness to multiple anticonvulsant drugs. (Supported by NS039516 (TNF).)