Synaptic zinc contributes to motor and cognitive deficits in 6- hydroxydopamine mouse models of Parkinson's disease
authors
keywords
- Synaptic zinc
- Striatum
- Motor behavior
- Recognition memory
- 6-OHDA
- Mice
- Parkinson's disease
document type
ARTabstract
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 2+ as a co-transmitter alongside glutamate, but the role of synaptically released Zn 2+ 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 2+ 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 2+ contributes to behavioral deficits but not neu-rotoxic effects of 6-OHDA. To gain further insight into the mechanisms of Zn 2+ actions, we used the extracellular Zn 2+ chelator CaEDTA and knock-in mice lacking the high affinity Zn 2+ inhibition of GluN2A-containing NMDA receptors (GluN2A-NMDARs). Acute chelation of extracellular Zn 2+ in the striatum restored locomotor deficit of 6-OHDA lesion, confirming that synaptic Zn 2+ suppresses locomotor behavior. Disruption of the Zn 2+-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 2+ in the pathophysiology of PD. They unveil that synaptic Zn 2+ plays predominantly a detrimental role by promoting motor and cognitive deficits caused by nigrostriatal DA denervation, pointing towards new therapeutic interventions.
