Zhong Ping, Hu Zhixing, Jiang Houbo, Yan Zhen, Feng Jian
Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA; Veterans Affairs Western New York Healthcare System, Buffalo, NY 14215, USA.
Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA; Veterans Affairs Western New York Healthcare System, Buffalo, NY 14215, USA.
Cell Rep. 2017 May 2;19(5):1033-1044. doi: 10.1016/j.celrep.2017.04.023.
Locomotor symptoms in Parkinson's disease (PD) are accompanied by widespread oscillatory neuronal activities in basal ganglia. Here, we show that activation of dopamine D1-class receptors elicits a large rhythmic bursting of spontaneous excitatory postsynaptic currents (sEPSCs) in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations, but not normal subjects. Overexpression of wild-type parkin, but not its PD-causing mutant, abolishes the oscillatory activities in patient neurons. Dopamine induces a delayed enhancement in the amplitude of spontaneous, but not miniature, EPSCs, thus increasing quantal content. The results suggest that presynaptic regulation of glutamatergic transmission by dopamine D1-class receptors is significantly potentiated by parkin mutations. The aberrant dopaminergic regulation of presynaptic glutamatergic transmission in patient-specific iPSC-derived midbrain neurons provides a mechanistic clue to PD pathophysiology, and it demonstrates the usefulness of this model system in understanding how mutations of parkin cause movement symptoms in Parkinson's disease.
帕金森病（PD）的运动症状伴随着基底神经节广泛的振荡性神经元活动。在此，我们表明多巴胺D1类受体的激活会在源自帕金森病患者（携带帕金突变）而非正常受试者的诱导多能干细胞（iPSC）分化的中脑神经元中引发大量有节律的自发性兴奋性突触后电流（sEPSC）爆发。野生型帕金的过表达而非其导致帕金森病的突变体的过表达，消除了患者神经元中的振荡活动。多巴胺诱导自发性而非微小兴奋性突触后电流（EPSC）幅度的延迟增强，从而增加量子含量。结果表明，帕金突变显著增强了多巴胺D1类受体对谷氨酸能传递的突触前调节。患者特异性iPSC衍生的中脑神经元中突触前谷氨酸能传递的异常多巴胺能调节为帕金森病的病理生理学提供了一个机制线索，并且证明了该模型系统在理解帕金突变如何导致帕金森病运动症状方面的有用性。
