Li Lijun, Fan Mannie, Icton Carolyn D, Chen Nansheng, Leavitt Blair R, Hayden Michael R, Murphy Tim H, Raymond Lynn A
Kinsmen Laboratories, Department of Psychiatry, University of British Columbia, 4N3-2255 Westbrook Mall, BC, Vancouver, Canada V6T 1Z3.
Neurobiol Aging. 2003 Dec;24(8):1113-21. doi: 10.1016/j.neurobiolaging.2003.04.003.
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.
N-甲基-D-天冬氨酸受体（NMDAR）介导的兴奋性毒性被认为在亨廷顿舞蹈症（HD）中起作用，HD由亨廷顿蛋白中多聚谷氨酰胺序列的扩增引起。HD的特征是选择性神经退行性变，最严重影响纹状体中型棘状投射神经元（MSN），其中NMDAR亚基NR2B的表达相对于其他NR2亚基增加。在此，我们回顾我们的数据，即NR2B型NMDAR电流在转染的非神经元细胞以及来自HD的YAC72转基因小鼠模型的急性分离的纹状体MSN中被突变型亨廷顿蛋白选择性增强。同样，我们报告与野生型小鼠相比，来自YAC72的皮质纹状体切片记录中纹状体MSN的NMDAR介导的突触电流增加。这种效应与更大的NMDAR与AMPA受体介导的电流比率相关，表明突触后NMDAR的特异性增强。增强的NMDAR电流可能涉及表面受体数量或活性的增加，因为我们在纹状体NR2B表达中未观察到基因型之间的差异。在表达突变型亨廷顿蛋白的纹状体MSN中含NR2B的NMDAR电流的增强可能有助于解释这些神经元在HD中对变性的极度易感性。
