Cellular Neurobiology Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, U.S. Department of Health and Human Services, Baltimore, MD 21224, USA.
FASEB J. 2011 Apr;25(4):1333-44. doi: 10.1096/fj.10-173625. Epub 2011 Jan 13.
Parkinson's disease (PD) involves progressive loss of nigrostriatal dopamine (DA) neurons over an extended period of time. Mitochondrial damage may lead to PD, and neurotoxins affecting mitochondria are widely used to produce degeneration of the nigrostriatal circuitry. Deletion of the mitochondrial transcription factor A gene (Tfam) in C57BL6 mouse DA neurons leads to a slowly progressing parkinsonian phenotype in which motor impairment is first observed at ~12 wk of age. L-DOPA treatment improves motor dysfunction in these "MitoPark" mice, but this declines when DA neuron loss is more complete. To investigate early neurobiological events potentially contributing to PD, we compared the neurochemical and electrophysiological properties of the nigrostriatal circuit in behaviorally asymptomatic 6- to 8-wk-old MitoPark mice and age-matched control littermates. Release, but not uptake of DA, was impaired in MitoPark mouse striatal brain slices, and nigral DA neurons lacked characteristic pacemaker activity compared with control mice. Also, hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel function was reduced in MitoPark DA neurons, although HCN messenger RNA was unchanged. This study demonstrates altered nigrostriatal function that precedes behavioral parkinsonian symptoms in this genetic PD model. A full understanding of these presymptomatic cellular properties may lead to more effective early treatments of PD.
帕金森病（PD）涉及黑质纹状体多巴胺（DA）神经元在较长时间内的进行性丧失。线粒体损伤可能导致 PD，并且影响线粒体的神经毒素被广泛用于产生黑质纹状体回路的退化。C57BL6 小鼠 DA 神经元中线粒体转录因子 A 基因（Tfam）的缺失导致帕金森病表型的缓慢进展，其中运动功能障碍首先在~12 周龄时观察到。L-DOPA 治疗可改善这些“MitoPark”小鼠的运动功能障碍，但当 DA 神经元丢失更完全时，这种改善会下降。为了研究可能导致 PD 的早期神经生物学事件，我们比较了行为无症状的 6-8 周龄 MitoPark 小鼠和年龄匹配的对照同窝仔鼠的黑质纹状体回路的神经化学和电生理特性。与对照小鼠相比，MitoPark 小鼠纹状体脑切片中的 DA 释放，但摄取没有受损，并且黑质 DA 神经元缺乏特征性起搏活动。此外，MitoPark DA 神经元中的超极化激活环核苷酸门控（HCN）离子通道功能降低，尽管 HCN 信使 RNA 没有改变。这项研究表明，在这种遗传 PD 模型中，行为性帕金森病症状之前存在黑质纹状体功能改变。对这些无症状细胞特性的全面了解可能会导致更有效的 PD 早期治疗。
