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Age-Dependent Resistance to Excitotoxicity in Htt CAG140 Mice and the Effect of Strain Background

Article type: Research Article

Authors: Strong, Melissa K.; | Southwell, Amber L. | Yonan, Jennifer M. | Hayden, Michael R. | MacGregor, Grant R.; ; | Thompson, Leslie M.; ; ; | Steward, Oswald; ; ;

Affiliations: Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA, USA | Reeve-Irvine Research Center, University of California Irvine, Irvine, CA, USA | Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada | Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA | Developmental Biology Center, University of California Irvine, Irvine, CA, USA | Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA | Department of Psychiatry and Human Behavior and Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA | Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA | Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA | Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, USA

Note: [] Correspondence to: Oswald Steward, 1101 Gillespie Neuroscience Research Facility, University of California, Irvine Anatomy & Neurobiology Irvine, CA 92697-4265, USA. Tel.: +1 949 824 8908; Fax: +1 949 824 2625; E-mail: osteward@uci.edu

Keywords: Excitotoxin, Huntington's disease, inbred mouse strains, resistance, cell death, neurodegeneration, genetic background

DOI: 10.3233/JHD-129005

Journal: Journal of Huntington's Disease, vol. 1, no. 2, pp. 221-241, 2012

Published: 2012
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Abstract

Mouse strain background can influence vulnerability to excitotoxic neuronal cell death and potentially modulate phenotypes in transgenic mouse models of human disease. Evidence supports a contribution of excitotoxicity to the selective death of medium spiny neurons in Huntington's disease (HD). Here, we assess whether strain differences in excitotoxic vulnerability influence striatal cell death in a knock-in mouse model of HD. Previous studies that evaluated resistance to excitotoxic lesions in several mouse models of HD had variable outcomes. In the present study, we directly compare one model on two different background strains to test the contribution of strain to excitotoxicity-mediated neurodegeneration. Mice of the FVB/N strain, which are highly vulnerable to excitotoxicity, become extremely resistant to quinolinic acid-induced striatal neurodegeneration with age, when carrying a huntingtin (Htt) allele expressing a HD transgene (CAG140). The resistance is much greater than the age-dependent resistance that has been previously reported in YAC128 mice. By 12 months of age, both heterozygous and homozygous FVB.CAG140 mice displayed virtually complete resistance to quinolinic acid-induced striatal neurodegeneration. A similar resistance develops in CAG140 mice on a C57BL/6N background although the effect size is smaller because C57BL/6N mice are already resistant due to genetic background. In a direct comparison with the YAC128 mice, FVB.CAG140 mice have greater resistance. FVB.CAG140 mice are also resistant to neurodegeneration following kainic acid-induced status epilepticus suggesting the existence of a common cellular mechanism that provides protection against multiple types of excitotoxic insult. These findings establish FVB.CAG140 mice as a useful model to investigate the cellular and molecular mechanisms that confer neuroprotection against excitotoxicity.

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