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 F1 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.
Schauwecker
Paula Elyse
PE
Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street, BMT 401, Los Angeles, CA 90089-9112, USA. schauwec@usc.edu
D000818:Animals; D002452:Cell Count; D016923:Cell Death; D002678:Chimera; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005452:Fluoresceins; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009410:Nerve Degeneration / Q000209:etiology* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009930:Organic Chemicals; D010641:Phenotype; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D013045:Species Specificity; D013194:Staining and Labeling; D013997:Time Factors
D018690:Excitatory Amino Acid Agonists; D005452:Fluoresceins; D005456:Fluorescent Dyes; D009930:Organic Chemicals; C435731:fluoro jade; D007608:Kainic Acid