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.
Highlights
Epilepsy is a chronic neurologic disorder characterized by the occurrence of spontaneous recurrent seizures, which consist of prolonged and synchronized neuronal discharges
To examine if and how these loci cooperate in the context of seizure-induced cell death, a double congenic strain, FVB.B6Sicd1/Sicd2, was generated
To determine if seizure severity was modulated in a double congenic strain, FVB.B6-Sicd1/Sicd2 mice were treated with kainic acid and we examined whether significant differences in latency to the onset of the first severe seizure or duration of severe seizures differed significantly from the single congenic strains Sicd1 and Sicd2
Summary
Epilepsy is a chronic neurologic disorder characterized by the occurrence of spontaneous recurrent seizures, which consist of prolonged and synchronized neuronal discharges. The most common form of epilepsy is temporal lobe epilepsy (TLE), a catastrophic disorder characterized by pharmacologically intractable seizures and progressive cognitive impairment. TLE-associated brain damage is caused by persistent and highly repetitive seizures that are associated with excitotoxic cell death mechanisms. While recent genetic discoveries have led to significant insight into molecular pathways of likely importance in epilepsy pathogenesis [4], these discoveries have not contributed to an understanding of molecular mechanisms that result in seizure-induced cell death. The use of inbred mouse strains provides a more tractable approach for investigating disease loci
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