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). 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.
Heng
Mary Y
MY
Neuroscience Graduate Program and Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Detloff
Peter J
PJ
Wang
Phillip L
PL
Tsien
Joe Z
JZ
Albin
Roger L
RL
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate