Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Neuron. 2010 Jan 28;65(2):178-90. doi: 10.1016/j.neuron.2010.01.008.
N-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation promotes cell death. We report specifically increased extrasynaptic NMDAR expression, current, and associated reductions in nuclear CREB activation in HD mouse striatum. The changes are observed in the absence of dendritic morphological alterations, before and after phenotype onset, correlate with mutation severity, and require caspase-6 cleavage of mutant huntingtin. Moreover, pharmacological block of extrasynaptic NMDARs with memantine reversed signaling and motor learning deficits. Our data demonstrate elevated extrasynaptic NMDAR activity in an animal model of neurodegenerative disease. We provide a candidate mechanism linking several pathways previously implicated in HD pathogenesis and demonstrate successful early therapeutic intervention in mice.
N-甲基-D-天冬氨酸受体（NMDAR）兴奋性毒性与亨廷顿病（HD）的发病机制有关，HD 是一种迟发性神经退行性疾病。然而，由于 NMDAR 在生理上的重要作用，它们并不是理想的治疗靶点。最近的研究表明，突触 NMDA 受体传递驱动神经保护基因转录，而突触外 NMDA 受体激活则促进细胞死亡。我们特别报告了在 HD 小鼠纹状体中，突触外 NMDAR 表达、电流增加，以及核 CREB 激活减少。这些变化在表型出现之前和之后都没有观察到树突形态的改变，与突变的严重程度相关，并且需要 caspase-6 切割突变的 huntingtin。此外，用美金刚阻断突触外 NMDAR 可以逆转信号转导和运动学习缺陷。我们的数据表明，在神经退行性疾病的动物模型中存在升高的突触外 NMDAR 活性。我们提供了一个候选机制，将先前与 HD 发病机制相关的几个途径联系起来，并在小鼠中成功进行了早期治疗干预。
