Activity of the manganese efflux transporter SLC30A10 in dopaminergic but not GABAergic neurons protects against neurotoxicity

Metals such as copper, iron, and manganese (Mn) are essential for life, but induce neurotoxicity at elevated levels. Yet, the neuronal mechanisms of metal-induced neurological disease are largely unclear. A primary limitation has been an inability to selectively alter metal levels in specific neurons, so that the role of the targeted neurons in disease biology can be isolated. Here, we show that neuron-specific depletion of metal efflux transporters provides the feasibility to overcome this limitation by focusing on Mn, which accumulates in the basal ganglia and induces motor disease, and the Mn-specific efflux transporter SLC30A10. Pan-neuronal/glial Slc30a10 knockout mice exhibited increased basal ganglia Mn levels and hypolocomotor deficits in early-life (pre-adulthood), which were exacerbated by Mn exposure. The locomotor deficits of the pan-neuronal/glial strain was associated with a reduction in evoked striatal dopamine release without dopaminergic (DAergic) neurodegeneration or changes in striatal tissue dopamine levels. Furthermore, DAergic-specific, but not GABAergic-specific, Slc30a10 knockout mice recapitulated the hypolocomotor phenotype of the pan-neuronal/glial knockouts in early-life although Mn levels were elevated in the targeted basal ganglia regions of both the neuron-specific strains. Put together, our results imply that (1) activity of SLC30A10 in DAergic neurons is necessary to protect against early-life Mn neurotoxicity; (2) increasing Mn levels in DAergic neurons is sufficient to induce early-life motor disease, suggesting that Mn targets DAergic neurons in the early-life period to induce motor deficits; and (3) neuron-specific knockout of metal efflux transporters may be a widely applicable strategy to elucidate mechanisms of metal-induced neurotoxicity.