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J Neurosci. 2009 Mar 11;29(10):3200-5. doi: 10.1523/JNEUROSCI.5599-08.2009.

In vivo evidence for NMDA receptor-mediated excitotoxicity in a murine genetic model of Huntington disease.

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  • 1Neuroscience Graduate Program and Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, USA.

Abstract

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.

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