Synaptic zinc contributes to motor and cognitive deficits in 6-hydroxydopamine mouse models of Parkinson's disease.
Title | Synaptic zinc contributes to motor and cognitive deficits in 6-hydroxydopamine mouse models of Parkinson's disease. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Sikora J, Kieffer BL, Paoletti P, Ouagazzal A-M |
Journal | Neurobiol Dis |
Volume | 134 |
Pagination | 104681 |
Date Published | 2019 Nov 20 |
ISSN | 1095-953X |
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 Zn as a co-transmitter alongside glutamate, but the role of synaptically released Zn 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 Zn 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 Zn contributes to behavioral deficits but not neurotoxic effects of 6-OHDA. To gain further insight into the mechanisms of Zn actions, we used the extracellular Zn chelator CaEDTA and knock-in mice lacking the high affinity Zn inhibition of GluN2A-containing NMDA receptors (GluN2A-NMDARs). Acute chelation of extracellular Zn in the striatum restored locomotor deficit of 6-OHDA lesion, confirming that synaptic Zn suppresses locomotor behavior. Disruption of the Zn-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 Zn in the pathophysiology of PD. They unveil that synaptic Zn plays predominantly a detrimental role by promoting motor and cognitive deficits caused by nigrostriatal DA denervation, pointing towards new therapeutic interventions. |
DOI | 10.1016/j.nbd.2019.104681 |
Alternate Journal | Neurobiol. Dis. |
PubMed ID | 31759136 |