Get access

Genetic control of sensitivity to hippocampal cell death induced by kainic acid: A quantitative trait loci analysis

Authors

  • Paula Elyse Schauwecker,

    Corresponding author
    1. Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles, California 90089-9112
    • Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90089-9112
    Search for more papers by this author
  • Robert W. Williams,

    1. Center for Neuroscience, Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163
    Search for more papers by this author
  • Julia Belen Santos

    1. Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles, California 90089-9112
    Search for more papers by this author

Abstract

Host genetic factors are likely to contribute to differences in individual susceptibility to seizure-induced excitotoxic neuronal damage. Similarly, inbred strains of mice differ in their susceptibility to the kainic acid (KA) model of seizure-induced cell death, but the genes responsible for the differences are not known. Here, we define the inheritance patterns of susceptibility to KA-induced neurodegeneration in the hippocampus by assessing 331 back-cross (N2) progeny of two inbred mouse strains, C57BL/6 and FVB/N, previously shown to display resistance and sensitivity to KA-induced cell death, respectively. Results of phenotypic analysis suggest that the difference in susceptibility between these two strains is conferred by a single dominant gene. Therefore, we used an N2 back-cross between the inbred C57BL/6 and FVB/N strains for a genome-wide search for quantitative trait loci (QTLs), which are chromosomal sites containing genes influencing the magnitude of susceptibility. Genome-wide interval mapping in N2 progeny identified a locus on distal chromosome (Chr) 18 with a peak LOD score of 4.9 localized between D18Mit186 and D18Mit4 as having the strongest and most significant effect in this model. QTLs of minor effect were detected on Chr 15 (D15Mit174-D15Mit156) and Chr 4 (D4Mit264-D4Mit91), with peak LOD scores of 3.02 and 2.46, respectively. The three significant QTLs (Chrs 4, 15, 18) together account for nearly 25% of the trait variance for both genders combined. Reduced KA-induced cell death susceptibility was observed in a congenic strain in which the highly susceptible FVB/N strain carried putative resistance alleles from the C57BL/6 strain on Chr 18. J. Comp. Neurol. 477:96–107, 2004. © 2004 Wiley-Liss, Inc.

Ancillary