Abstracts

RATIONALE: We have documented previously via QTL mapping that the distal region of chr.1 contains a gene(s) that mediates the profound differences between C57BL/6 (B6) and DBA/2 (D2) inbred strains of mice regarding their sensitivity to seizures induced by kainic acid, pentylenetetrazol (PTZ) and electroconvulsive shock (ECS). To begin to study this factor further, we generated reciprocal congenic strains (CSs) between B6 and D2 mice using a marker-assisted backcross-introgression strategy.
METHODS: DNA markers used for selection up to generation N9 spanned a large interval (D1Mit7 to D1Mit17). N9 recombinants were identified and a panel of recombinant CSs were propagated by brother-sister mating at N10. N10 mice were tested for maximal seizure response to a single injection of PTZ (80 mg/kg, sc) or for maximal electroshock threshold using a standard one-shock per day ramp-up ECS procedure.
RESULTS: So far, results show that introgression of distal chr.1 markers from the seizure-sensitive D2 strain onto a seizure-resistant B6 genetic background transfers enhanced seizure responsiveness to PTZ and lower ECS threshold. Studies of reciprocal recombinant CSs have led to identification of D1Mit110 and D1Mit17 as markers which flank the critical interval. Candidate genes in the region include Kcnj10, Kcnj9, Atp1a2 and Atp1a4. Strain differences in the coding sequence of genes are being used to narrow the critical interval. Studies of the commercially available CS B6.D2-Mtv7a/Ty have helped to further refine the map position of the chr.1 seizure-related QTL to a region bounded by Kcnj10 (93 cM) and D1Mit17 (106 cM).
CONCLUSIONS: We conclude that this interval contains a gene(s) largely responsible for mediating the difference in seizure sensitivity between B6 and D2 mice.
Support: Supported by NIH grants NS33243 and NS40554