title: Susceptibility to seizure-induced excitotoxic cell death is regulated by an epistatic interaction between Chr 18 (Sicd1) and Chr 15 (Sicd2) loci in mice.
abstract: Seizure-induced cell death is believed to be regulated by multiple genetic components in addition to numerous external factors. We previously defined quantitative trait loci that control susceptibility to seizure-induced cell death in FVB/NJ (susceptible) and C57BL/6J (resistant) mice. Two of these quantitative trait loci assigned to chromosomes 18 (Sicd1) and 15 (Sicd2), control seizure-induced cell death resistance. In this study, through the use of a series of novel congenic strains containing the Sicd1 and Sicd2 congenic strains and different combinations of the Sicd1 or Sicd2 sub region(s), respectively, we defined these genetic interactions. We generated a double congenic strain, which contains the two C57BL/6J differential segments from chromosome 18 and 15, to determine how these two segments interact with one another. Phenotypic comparison between FVB-like littermates and the double congenic FVB.B6-Sicd1/Sicd2 strain identified an additive effect with respect to resistance to seizure-induced excitotoxic cell death. It thus appears that C57BL/6J alleles located on chromosomes 18 and 15 interact epistatically in an additive manner to control the extent of seizure-induced excitotoxic cell death. Three interval-specific congenic lines were developed, in which either segments of C57BL/6J Chr 18 or C57BL/6J Chr 15 were introduced in the FVB/NJ genetic background, and progeny were treated with kainate and examined for the extent of seizure-induced cell death. All of the interval-specific congenic lines exhibited reduced cell death in both area CA3 and the dentate hilus, associated with the C57BL/6J phenotype. These experiments demonstrate functional interactions between Sicd1 and Sicd2 that improve resistance to seizure-induced excitotoxic cell death, validating the critical role played by gene-gene interactions in excitotoxic cell death.
authors.affiliation: Department of Cell and Neurobiology, USC Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Paula Elyse
authors.initials: PE
authors.lastname: Schauwecker
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D016923:Cell Death / Q000235:genetics; D033481:Chromosomes, Mammalian; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D056426:Genetic Loci; D005838:Genotype; D006624:Hippocampus / Q000473:pathology; D007608:Kainic Acid / Q000009:adverse effects; D051379:Mice; D018895:Microsatellite Repeats; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D020161:Physical Chromosome Mapping; D040641:Quantitative Trait Loci; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000523:psychology
chemical_list: D007608:Kainic Acid