The ZIP3 Zinc Transporter Is Localized to Mossy Fiber Terminals and Is Required for Kainate-Induced Degeneration of CA3 Neurons

Tight regulation of neuronal Zn²¹ is critical for physiological function. Multiple Zn²¹ transporters are expressed in the brain, yet their spatial distribution and distinct roles are largely unknown. Here, we show developmental regulation of the expression of Zn²¹ transporters ZIP1 and ZIP3 in mouse hippocampal neurons, corresponding to previously described increase in neuronal vesicular Zn²¹ during the first postnatal month. Rates of Zn²¹ uptake in cultured mouse hippocampal neurons, monitored using FluoZin-3 fluorescence, were higher in mature neurons, which express higher levels of ZIP1 and ZIP3. Zn²1 uptake was attenuated by;50% following silencing of either ZIP1 or ZIP3. Expression of both ZIP1 and ZIP3 was ubiquitous on somas and most neuronal processes in the cultured neurons. In contrast, we observed distinct localization of the transporters in adult mouse hippocampal brain, with ZIP1 predominantly expressed in the CA3 stratum pyramidale, and ZIP3 primarily localized to the stratum lucidum. Consistent with their localization, silencing of ZIP1 expression in vivo reduced Zn²¹ uptake in CA3 neurons while ZIP3 silencing reduced Zn²¹ influx into dentate gyrus (DG) granule cells in acute hippocampal slices. Strikingly, in vivo silencing of ZIP3, but not ZIP1, protected CA3 neurons from neurodegeneration following kainate-induced seizures. Our results indicate that distinct Zn²¹ transporters control Zn²¹ accumulation and toxicity in different neuronal populations in the hippocampus and suggest that selective regulation of Zn²¹ transporters can prevent seizure induced brain damage.