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The Journal of Neuroscience, February 18, 2009, 29(7):2193-2204; doi:10.1523/JNEUROSCI.5473-08.2009
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Neurobiology of Disease
Differential Susceptibility to Excitotoxic Stress in YAC128 Mouse Models of Huntington Disease between Initiation and Progression of Disease
Rona K. Graham,1 Mahmoud A. Pouladi,1 Prasad Joshi,3 Ge Lu,1 Yu Deng,1 Nan-Ping Wu,3 Bryan E. Figueroa,4 Martina Metzler,1 Véronique M. André,3 Elizabeth J. Slow,1 Lynn Raymond,2 Robert Friedlander,4 Michael S. Levine,3 Blair R. Leavitt,1 * andMichael R. Hayden1 * 1Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, and 2Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4, 3Mental Retardation Research Center, University of California, Los Angeles, Los Angeles, California 90024, and 4Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
Correspondence should be addressed to either Blair R. Leavitt or Michael R. Hayden, Centre for Molecular Medicine and Therapeutics, University of British Columbia, 980 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4, Email: bleavitt{at}cmmt.ubc.ca or Email: mrh{at}cmmt.ubc.ca
Huntington disease (HD) is a neurodegenerative disorder caused by an expanded CAG tract in the HD gene. Polyglutamine expansion of huntingtin (htt) results in early, progressive loss of medium spiny striatal neurons, as well as cortical neurons that project to the striatum. Excitotoxicity has been postulated to play a key role in the selective vulnerability of striatal neurons in HD. Early excitotoxic neuropathological changes observed in human HD brain include increased quinolinate (QUIN) concurrent with proliferative changes such as increased spine density and dendritic length. In later stages of the disease, degenerative-type changes are apparent, such as loss of dendritic arborization, a reduction in spine density and reduced levels of 3-hydroxykynurenine and QUIN. It is currently unknown whether sensitivity to excitotoxic stress varies between initiation and progression of disease. Here, we have assessed the excitotoxic phenotype in the YAC128 mouse model of HD by examining the response to excitotoxic stress at different stages of disease. Our results demonstrate that YAC128 mice display enhanced sensitivity to NMDA ex vivo and QUIN in vivo before obvious phenotypic changes. In contrast, 10-month-old symptomatic YAC128 mice are resistant to QUIN-induced neurotoxicity. These findings are paralleled by a significant increase in NMDAR-mediated membrane currents in presymptomatic YAC128 dissociated medium spiny neurons progressing to reduced NMDAR-mediated membrane currents with disease progression. These data highlight the dynamic nature of the mutant htt-mediated excitotoxic phenotype and suggests that therapeutic approaches to HD may need to be altered, depending on the stage and development of the disease.
Key words: Huntington disease; excitotoxicity; mouse models; ischemia; mutant huntingtin; quinolinate
Received Nov. 12, 2008; revised Jan. 7, 2009; accepted Jan. 11, 2009.
Correspondence should be addressed to either Blair R. Leavitt or Michael R. Hayden, Centre for Molecular Medicine and Therapeutics, University of British Columbia, 980 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4, Email: bleavitt{at}cmmt.ubc.ca or Email: mrh{at}cmmt.ubc.ca
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