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Use of chromosome substitution strains to identify seizure susceptibility loci in mice

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Abstract

Seizure susceptibility varies among inbred mouse strains. Chromosome substitution strains (CSS), in which a single chromosome from one inbred strain (donor) has been transferred onto a second strain (host) by repeated backcrossing, may be used to identify quantitative trait loci (QTLs) that contribute to seizure susceptibility. QTLs for susceptibility to pilocarpine-induced seizures, a model of temporal lobe epilepsy, have not been reported, and CSS have not previously been used to localize seizure susceptibility genes. We report QTLs identified using a B6 (host) × A/J (donor) CSS panel to localize genes involved in susceptibility to pilocarpine-induced seizures. Three hundred fifty-five adult male CSS mice, 58 B6, and 39 A/J were tested for susceptibility to pilocarpine-induced seizures. Highest stage reached and latency to each stage were recorded for all mice. B6 mice were resistant to seizures and slower to reach stages compared to A/J mice. The CSS for Chromosomes 10 and 18 progressed to the most severe stages, diverging dramatically from the B6 phenotype. Latencies to stages were also significantly shorter for CSS10 and CSS18 mice. CSS mapping suggests seizure susceptibility loci on mouse Chromosomes 10 and 18. This approach provides a framework for identifying potentially novel homologous candidate genes for human temporal lobe epilepsy.

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Acknowledgments

This work was supported by grants K02 NS050429 and MH70933. The authors thank Dr. John Belknap for his statistical expertise and assistance.

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Authors and Affiliations

  1. Department of Neurology, Columbia University, New York, New York, 10032, USA

    Melodie R. Winawer & Martin Niethammer

  2. Department of Pediatric Neurology, Columbia University, New York, New York, 10032, USA

    Rachel Kuperman

  3. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, 10032, USA

    Steven Sherman

  4. Department of Statistics, Columbia University, New York, New York, 10032, USA

    Daniel Rabinowitz & Irene Plana Guell

  5. Department of Genetics and Development, Columbia University, New York, New York, 10032, USA

    Christine A. Ponder

  6. Department of Human Genetics, University of Chicago, Chicago, Illinois, 60637, USA

    Abraham A. Palmer

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  1. Melodie R. Winawer
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Correspondence to Melodie R. Winawer.

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Winawer, M.R., Kuperman, R., Niethammer, M. et al. Use of chromosome substitution strains to identify seizure susceptibility loci in mice. Mamm Genome 18, 23–31 (2007). https://doi.org/10.1007/s00335-006-0087-6

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