MAPPING MURINE LOCI FOR SEIZURE RESPONSE TO KAINIC ACID

Mature DBA/2J (D2) mice are very sensitive to seizures induced by vari ous chemical and physical stimuli, whereas C57BL/6J (B6) mice are rela tively seizure resistant. We have con ducted a genome-wide search for quantitative bait loci (QTLs) influencing the differential sensitivity of these strains to kainic acid (KA)-induced seizures by studying an F-2 intercross population, Parental, F-1, and F-2 mice (8-10 weeks of age) were injected subcutaneously with 25 mg/kg of KA and observed for 3 h. Latencies to focal and generalized seizures and status epileptic us were recorded and used to calculate an overall seizure score, Resul ts of seizure testing indicated that the difference in susceptibility to I(A-induced seizures between D2 and B6 mice is a polygenic phenomen on with at least 65% of the variance due to genetic factors. First-pas s genome screening (10-cM marker intervals) in F-2 progeny (n = 257) d ocumented a QTL of moderate effect on Chromosome (Chr) 1 with a peak L OD score of 5.5 (17% of genetic variance explained) localized between D1Mit30 and D1Mit16. Provisional QTLs of small effect were detected on Chr 11 (D11Mit224-D11Mit14), 15 (D15Mir6-D15Mit46) and 18 (D18Mit9-D1 8Mit144). Multiple locus models generally confirmed the Mapmaker/QTL r esults and also provided evidence for another QTL on Chr 4 (D411Mit9). Multilocus analysis of seizure severity suggested that additional loc i on Chrs 5 (D5Mit11), 7 (D7Mit66), and 15 (D15Nds2) might also contri bute to KA-induced seizure response. Overall, our results document a c omplex genetic determinism for KA-induced seizures in these mouse stra ins with contributions from as many as eight QTLs.