Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene

The mammalian protein ZnT3 resides on synaptic vesicle membranes of zinc-co ntaining neurons, suggesting its possible role in vesicular zinc transport, We show here that histochemically reactive zinc, corresponding to the zinc found within synaptic vesicles, was undetectable in the brains of mice wit h targeted disruption of the ZnT3 gene. Total zinc levels in the hippocampu s and cortex of these mice were reduced by about 20%. The ultrastructure of mossy fiber boutons, which normally store the highest levels of vesicular zinc, was unaffected. Mice with one normal ZnT3 allele had reduced levels o f ZnT3 protein an synaptic vesicle membranes and had intermediate amounts o f vesicular zinc. These results demonstrate that ZnT3 is required for trans port of zinc into synaptic vesicles and suggest that vesicular zinc concent ration is determined by the abundance of ZnT3.