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Synaptic zinc contributes to motor and cognitive deficits in 6-hydroxydopamine mouse models of Parkinson's disease

Abstract : 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.
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Submitted on : Tuesday, January 14, 2020 - 2:01:38 PM
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Joanna Sikora, Brigitte L. Kieffer, Pierre Paoletti, Abdel-Mouttalib Ouagazzal. Synaptic zinc contributes to motor and cognitive deficits in 6-hydroxydopamine mouse models of Parkinson's disease. Neurobiology of Disease, Elsevier, 2020, 134, pp.104681. ⟨10.1016/j.nbd.2019.104681⟩. ⟨inserm-02438938⟩



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