Objective: The potential involvement of synaptic Zn²⁺ in development of Parkinson’s disease (PD) motor symptoms and dopaminergic neurodegeneration was investigated.

Background: The progressive degeneration of nigrostriatal dopaminergic pathway in PD results in a compensatory overactivity of glutamatergic cortico-striatal pathways that contributes to the expression of the clinical motor symptoms and neurotoxicity leading to dopaminergic (DA) cell death. Subset of glutamatergic cortico-striatal projection neurons uses ionic Zn²⁺ as a co-transmitter, but its role in PD remains unexplored.

Method: Zn²⁺ transporter-3 (ZnT3) knockout mice were used to investigate the impact of synaptic Zn²⁺ elimination on motor deficits and degeneration of nigrostriatal DA pathway induced by unilateral striatal 6-OHDA lesion. Intrastriatal infusions of the extracellular Zn²⁺ chelator, CaEDTA, and knock-in mice lacking high affinity Zn²⁺ inhibition of glutamatergic GluN2A-cantaining NMDA receptor were also used to gain further insight into the mechanisms of synaptic zinc actions.

Results: Genetic elimination of synaptic Zn²⁺ restores locomotor deficits induced by 6-OHDA lesion, an antiparkinsonian effect that was reproduced by pharmacological chelation of extracellular Zn²⁺ directly in the striatum. By contrast, it has no impact on degeneration of nigrostriatal DA terminals indicating that synaptically released Zn²⁺ promotes expression of motor deficits but not neurotoxicity of 6-OHDA lesion. Disruption of Zn²⁺ inhibitory action on GluN2A-NMDA receptors was without effect on locomotor deficits and neurotoxicity of 6-OHDA lesion. On the other hand, it exacerbated motor learning impairment.

Conclusion: These studies provide the first empirical evidence implicating synaptic Zn²⁺ in the pathophysiology of PD. They suggest that in PD condition synaptically released Zn²⁺ from cortico-striatal terminals may play predominantly a deleterious role alongside glutamate by promoting motor deficits of the disease. Such deleterious action of synaptic zinc may be mainly mediated through glutamatergic-independent mechanisms. The inhibitory action of synaptic zinc on GluN2A-NMDARs, the most zinc-sensitive glutamatergic receptor, is rather beneficial in the context of striatal dopamine depletion because dysfunction of these receptors contributes to development of motor deficits.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/synaptic-zn2-contribution-to-parkinsons-disease-pathophysiology-pharmacological-genetic-studies-in-preclinical-mouse-models/