In vivo evidence for NMDA receptor mediated excitotoxicity in a murine genetic model of Huntington Disease

N-methyl-D-aspartate receptor (NMDAR) mediated excitotoxicity is implicated as a proximate cause of neurodegeneration in Huntington Disease (HD). However, this hypothesis has not been tested rigorously in vivo. NMDAR NR2B-subunits are the predominant NR2 subunit expressed by the striatal medium spiny neurons that degenerate in HD. To test this 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. These results provide the first direct in vivo evidence of NR2B-NMDAR mediated excitotoxicity in the context of HD. Our results are consistent with prior suggestions that direct and/or indirect interactions of mutant huntingtin with NMDARs are a proximate cause of neurodegeneration in HD