Congenic strains provide evidence that a mapped locus on chromosome 15 influences excitotoxic cell death

Abstract

Inbred strains of mice differ in their susceptibility to excitotoxin-induced cell death, but the genetic basis of individual variation is unknown. Prior studies with crosses of the FVB/NJ (seizure-induced cell death susceptible) mouse and the seizure-induced cell death resistant mouse, C57BL/6J, showed the presence of three quantitative trait loci (QTLs), named seizure-induced cell death 1 (Sicd1) to Sicd3. To better localize and characterize the Sicd2 locus, two reciprocal congenic mouse strains were created. While the B6.FVB-Sicd2 congenic mouse was without effect on modifying susceptibility to seizure-induced excitotoxic cell death, the FVB.B6-Sicd2 congenic mouse, in which the chromosome (Chr) 15 region of C57BL/6J was introgressed into FVB/NJ, showed reduced seizure-induced excitotoxic cell death following kainate administration. Phenotypic comparison between FVB and the congenic FVB.B6-Sicd2 strain confirmed that the Sicd2 interval harbors gene(s) conferring strong protection against seizure-induced excitotoxic cell death. Interval-specific congenic lines (ISCLs) that encompass Sicd2 on Chr 15 were generated and were used to fine-map this QTL. Resultant progeny were treated with kainate and examined for the extent of seizure-induced cell death in order to deduce the Sicd2 genotypes of the recombinants through linkage analysis. All of the ISCLs exhibited reduced cell death associated with the C57BL/6J phenotype; however, ISCL-2 showed the most dramatic reduction in seizure-induced cell death in both area CA3 and in the dentate hilus. These findings confirm the existence of polymorphic loci within the reduced critical region of Sicd2 that regulate the severity of seizure-induced cell death.