Genetic basis of kainate-induced excitotoxicity in mice: phenotypic modulation of seizure-induced cell death

Excitotoxicity, a process in which excessive excitation of glutamate receptors results in cell death, has been implicated in a number of neurological disorders. However, the genetic characteristics and molecular mechanisms that can modulate the extent of cell death are unclear. Previously, we had reported that the extent of excitotoxic cell death is conferred by differences in the genetic background of several mouse strains. As a first step in the identification of loci that can modulate the extent of excitotoxin-induced cell death, we tested C57BL/6 and FVB/N mice, their F1 hybrids and backcross progeny for differences in apparent excitotoxic cell death induced by kainic acid (KA). While no strain dependent differences in seizure duration were observed. phenotypic analysis of cell death indicated that C57BL/6 mice showed no seizure-induced cell death, while FVB/N mice exhibited extensive cell death. Studies of seizure-induced cell death in hybrid and backcross progeny revealed an association between seizure-induced cell death and genotype. Mice from the F I cross exhibited little to no seizure-induced cell death. indicative that the extent of cell death is conferred as a dominant Genetic trait. Phenotypic assessment of cell death in backcross progeny suggests that differences in apparent cell death are conferred by a single gene locus. These findings implicate genetic factors in individual differences in excitotoxin-induced cell death. (C) 2003 Elsevier B.V. All rights reserved.