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The Journal of Neuroscience, March 11, 2009, 29(10):3200-3205; doi:10.1523/JNEUROSCI.5599-08.2009

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Brief Communications
In Vivo Evidence for NMDA Receptor-Mediated Excitotoxicity in a Murine Genetic Model of Huntington Disease

Mary Y. Heng,1,2 Peter J. Detloff,3 Phillip L. Wang,4 Joe Z. Tsien,4 and Roger L. Albin1,2,5

1Neuroscience Graduate Program and 2Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, 3Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 36294, 4Brain Discovery Institute, Medical College of Georgia, Augusta, Georgia 30912, and 5Geriatrics Research, Education, and Clinical Center, Veterans Affairs Ann Arbor Health System, Ann Arbor, Michigan 48105

Correspondence should be addressed to Dr. Roger L. Albin, 5023 Biomedical Science Research Building, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. Email: ralbin{at}umich.edu

N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity is implicated as a proximate cause of neurodegeneration in Huntington Disease (HD). This hypothesis has not been tested rigorously in vivo. NMDAR–NR2B subunits are a major NR2 subunit expressed by striatal medium spiny neurons that degenerate in HD. To test the excitotoxic hypothesis, we crossed a well validated murine genetic model of HD (Hdh(CAG)150) with a transgenic line overexpressing NMDAR–NR2B subunits. In the resulting double-mutant line, we show exacerbation of selective striatal neuron degeneration. This is the first direct in vivo evidence of NR2B–NMDAR-mediated excitotoxicity in the context of HD. Our results are consistent with previous suggestions that direct and/or indirect interactions of mutant huntingtin with NMDARs are a proximate cause of neurodegeneration in HD.

Received Nov. 22, 2008; revised Jan. 29, 2009; accepted Feb. 8, 2009.

Correspondence should be addressed to Dr. Roger L. Albin, 5023 Biomedical Science Research Building, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. Email: ralbin{at}umich.edu






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