Genetic basis of kainate-induced excitotoxicity in mice: phenotypic modulation of seizure-induced cell death
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1Department 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
Abstract:
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.
Insights
Genetic factors influence excitotoxic cell death. Differences in mouse strains show that susceptibility to excitotoxin-induced cell death is a dominant genetic trait, likely controlled by a single gene locus.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Excitotoxicity, driven by excessive glutamate receptor activation, contributes to neurological disorders.
- The genetic basis and molecular mechanisms controlling excitotoxic cell death remain largely unknown.
- Previous studies indicated that genetic background influences the severity of excitotoxic cell death.
Purpose of the Study:
- To identify genetic loci modulating excitotoxin-induced cell death.
- To investigate the genetic control of kainic acid-induced excitotoxicity.
- To determine if genetic factors contribute to differential susceptibility to excitotoxic neuronal death.
Main Methods:
- Comparative analysis of excitotoxic cell death in C57BL/6 and FVB/N mouse strains.
- Phenotypic assessment of kainic acid-induced seizure duration and neuronal cell death.
- Genotyping of F1 hybrid and backcross progeny to correlate genotype with cell death phenotype.
Main Results:
- C57BL/6 mice exhibited no kainic acid-induced seizure-related cell death, while FVB/N mice showed extensive cell death.
- F1 hybrids displayed minimal cell death, suggesting a dominant genetic trait controlling excitotoxic susceptibility.
- Backcross progeny analysis indicated that differences in cell death are likely conferred by a single gene locus.
Conclusions:
- Genetic background significantly impacts individual differences in excitotoxin-induced cell death.
- A single gene locus appears to control susceptibility to excitotoxic neuronal death.
- These findings highlight the role of specific genes in modulating neurological disorder outcomes.
