1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is known to selectively damage dopaminergic (DA) cells in the substantia nigra and to produce symptoms which are alike to those observed in Parkinson's disease (PD). Based on the similarity between MPTP-induced neurotoxicity and PD-related neuropathology, application of MPTP or its metabolite methyl-4-phenylpyridinium (MPP+) was successfully established in experimental rodent models to study PD-related neurodegenerative events. MPP+ is taken up by the dopamine transporter (DAT) into DA neurons where it exerts its neurotoxic action on mitochondria by affecting complex I of the respiratory chain. MPP+ is also a high affinity substrate for the serotonin transporter (SERT), however little is known about possible toxic effects of MPP+ on serotonergic (5-HT) neurons. In order to compare cell type-specific effects of MPP+ treatment, we have differentiated mouse embryonic stem (ES) cells into DA and 5-HT neurons and studied the impact of MPP+ treatment on both types of monoaminergic neurons in vitro. MPP+ treatment impacts on mitochondrial membrane potential in DA as well as 5-HT ES cell-derived neurons. Although mitochondria metabolisms are similarly affected, synaptic vesicle cycling is only impaired in DA ES cell-derived neurons. Most importantly we show that MPP+ induces DAT externalization in DA neurons, but internalization of SERT in 5-HT neurons. This diverse MPP+-induced transporter trafficking is reflected by elevated substrate uptake in DA neurons, and diminished substrate uptake in 5-HT neurons. In summary, our experimental data point toward differential effects of MPP+ intoxication on neurotransmitter release and re-uptake in different types of monoaminergic neurons.

中文翻译：

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甲基-4-苯基吡啶鎓（MPP +）差异影响小鼠胚胎干细胞衍生的多巴胺能和血清素能神经元中单胺的释放和再摄取。

已知1-甲基-4-苯基-1,2,5,6-四氢吡啶（MPTP）选择性损伤黑质中的多巴胺能（DA）细胞，并产生类似于帕金森氏病（PD）中观察到的症状。基于MPTP诱导的神经毒性与PD相关的神经病理学之间的相似性，成功地在实验啮齿动物模型中建立了MPTP或其代谢物甲基-4-苯基吡啶鎓（MPP +）的应用，以研究PD相关的神经退行性事件。MPP +被多巴胺转运蛋白（DAT）吸收到DA神经元中，在DA神经元中，MPP +通过影响呼吸链的复杂I对线粒体发挥神经毒性作用。MPP +还是5-羟色胺转运蛋白（SERT）的高亲和力底物，但是，关于MPP +对5-羟色胺能神经元（5-HT）神经元的潜在毒性作用知之甚少。为了比较MPP +处理对细胞类型的特异性作用，我们将小鼠胚胎干（ES）细胞分化为DA和5-HT神经元，并研究了MPP +处理对两种单胺能神经元的体外影响。MPP +处理会影响DA以及5-HT ES细胞源性神经元的线粒体膜电位。尽管线粒体的代谢受到类似的影响，但突触小泡循环仅在DA ES细胞来源的神经元中受到损害。最重要的是，我们表明MPP +诱导DA神经元中DAT的外在化，但诱导5-HT神经元中SERT的内在化。这种多样的MPP +诱导的转运蛋白运输通过DA神经元中底物摄取的增加和5-HT神经元中底物摄取的减少反映出来。总之，