Hyperactivity of glutamatergic corticostrial pathways is recognized as a key pathophysiological mechanism contributing to development of PD symptoms and dopaminergic neurotoxicity. Subset of corticostriatal projection neurons uses Zn2+ as a co-transmitter alongside glutamate, but the role of synaptically released Zn2+ in PD remains unexplored. We used genetically modified mice and pharmacological tools in combination with 6-hydroxydopamine (6-OHDA) lesion models of PD to investigate the contribution of synaptic zinc to disease associated behavioral deficits and neurodegeneration. Vesicular zinc transporter-3 (ZnT3) knockout mice lacking releasable Zn2+ were more resistant to locomotor deficit and memory impairment of nigrostriatal dopamine (DA) denervation compared to wildtype littermates. The loss of striatal dopaminergic fibers was comparable between genotypes, indicating that synaptically released Zn2+ contributes to behavioral deficits but not neurotoxic effects of 6-OHDA. To gain further insight into the mechanisms of Zn2+ actions, we used the extracellular Zn2+ chelator CaEDTA and knock-in mice lacking the high affinity Zn2+ inhibition of GluN2A-containing NMDA receptors (GluN2A-NMDARs). Acute chelation of extracellular Zn2+ in the striatum restored locomotor deficit of 6-OHDA lesion, confirming that synaptic Zn2+ suppresses locomotor behavior. Disruption of the Zn2+-GluN2A interaction had, on the other hand, no impact on locomotor deficit or neurotoxic effect of 6-OHDA. Collectively, these findings provide clear evidence for the implication of striatal synaptic Zn2+ in the pathophysiology of PD. They unveil that synaptic Zn2+ plays predominantly a detrimental role by promoting motor and cognitive deficits caused by nigrostriatal DA denervation, pointing towards new therapeutic interventions.

中文翻译：

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突触锌导致帕金森病 6-羟基多巴胺小鼠模型的运动和认知缺陷。

谷氨酸能皮质皮质通路的过度活跃被认为是导致 PD 症状和多巴胺能神经毒性发展的关键病理生理机制。皮质纹状体投射神经元的子集使用 Zn2+ 作为与谷氨酸盐一起的共递质，但突触释放的 Zn2+ 在 PD 中的作用仍未得到探索。我们使用转基因小鼠和药理学工具结合 PD 的 6-羟基多巴胺 (6-OHDA) 病变模型来研究突触锌对疾病相关行为缺陷和神经变性的贡献。与野生型同窝仔鼠相比，缺乏可释放 Zn2+ 的囊泡锌转运蛋白 3 (ZnT3) 敲除小鼠对黑质纹状体多巴胺 (DA) 去神经支配的运动缺陷和记忆障碍具有更强的抵抗力。纹状体多巴胺能纤维的损失在基因型之间相当，表明突触释放的 Zn2+ 导致行为缺陷，但不会导致 6-OHDA 的神经毒性作用。为了进一步了解 Zn2+ 作用的机制，我们使用了细胞外 Zn2+ 螯合剂 CaEDTA 和缺乏对含 GluN2A NMDA 受体 (GluN2A-NMDAR) 的高亲和力 Zn2+ 抑制的敲入小鼠。纹状体中细胞外 Zn2+ 的急性螯合恢复了 6-OHDA 损伤的运动缺陷，证实了突触 Zn2+ 抑制了运动行为。另一方面，破坏 Zn2+-GluN2A 相互作用对 6-OHDA 的运动缺陷或神经毒性作用没有影响。总的来说，这些发现为纹状体突触 Zn2+ 在 PD 的病理生理学中的意义提供了明确的证据。