Selenoprotein P (SELENOP1) is a selenium-rich antioxidant protein involved in extracellular transport of selenium (Se). SELENOP1 also has metal binding properties. The trace element Zinc (Zn²⁺) is a neuromodulator that can be released from synaptic terminals in the brain, primarily from a subset of glutamatergic terminals. Both Zn²⁺ and Se are necessary for normal brain function. Although these ions can bind together with high affinity, the biological significance of an interaction of SELENOP1 with Zn²⁺ has not been investigated. We examined changes in brain Zn²⁺ in SELENOP1 knockout (KO) animals. Timm-Danscher and N-(6-methoxy-8-quinolyl)-p-toluenesulphonamide (TSQ) staining revealed increased levels of intracellular Zn²⁺ in the SELENOP1^-/- hippocampus compared to wildtype (WT) mice. Mass spectrometry analysis of frozen whole brain samples demonstrated that total Zn²⁺ was not increased in the SELENOP1^-/- mice, suggesting only local changes in Zn²⁺ distribution. Unexpectedly, live Zn²⁺ imaging of hippocampal slices with a selective extracellular fluorescent Zn²⁺ indicator (FluoZin-3) showed that SELENOP1^-/- mice have impaired Zn²⁺ release in response to KCl-induced neuron depolarization. The zinc/metal storage protein metallothionein 3 (MT-3) was increased in SELENOP1^-/- hippocampus relative to wildtype, possibly in response to an elevated Zn²⁺ content. We found that depriving cultured cells of selenium resulted in increased intracellular Zn²⁺, as did inhibition of selenoprotein GPX4 but not GPX1, suggesting the increased Zn²⁺ in SELENOP1^-/- mice is due to a downregulation of antioxidant selenoproteins and subsequent release of Zn²⁺ from intracellular stores. Surprisingly, we found increased tau phosphorylation in the hippocampus of SELENOP1^-/- mice, possibly resulting from intracellular zinc changes. Our findings reveal important roles for SELENOP1 in the maintenance of synaptic Zn²⁺ physiology and preventing tau hyperphosphorylation.

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