Role of NR2B-type NMDA receptors in selective neurodegeneration in Huntington disease.
N-Methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity has been proposed to play a role in Huntington disease (HD), caused by expansion of a polyglutamine tract in the protein huntingtin. HD is characterized by selective neurodegeneration most severely affecting striatal medium-sized spiny projection neurons (MSNs), where expression of the NMDAR subunit NR2B is increased relative to other NR2 subunits. Here, we review our data that NR2B-type NMDAR currents are selectively potentiated by mutant huntingtin in transfected non-neuronal cells and acutely dissociated striatal MSNs from the YAC72 transgenic mouse model of HD. As well, we report increased striatal MSN NMDAR-mediated synaptic currents in corticostriatal slice recordings from YAC72 compared with wild-type mice. This effect was associated with a larger NMDAR- to AMPAR-mediated current ratio, suggesting specific potentiation of postsynaptic NMDARs. Enhanced NMDAR current likely involves increased surface receptor numbers or activity, since we observed no differences between genotypes in striatal NR2B expression. Potentiation of NR2B-containing NMDAR current in striatal MSNs expressing mutant huntingtin may help explain the exquisite vulnerability of these neurons to degeneration in HD.
Li
Lijun
L
Kinsmen Laboratories, Department of Psychiatry, University of British Columbia, 4N3-2255 Westbrook Mall, BC, Vancouver, Canada V6T 1Z3.
Fan
Mannie
M
Icton
Carolyn D
CD
Chen
Nansheng
N
Leavitt
Blair R
BR
Hayden
Michael R
MR
Murphy
Tim H
TH
Raymond
Lynn A
LA
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate