Dopamine (DA) transmission plays a critical role in processing rewarding and pleasurable stimuli. Increased synaptic DA release in the nucleus accumbens (NAc) is a central component of the physiological effects of drugs of abuse. The essential trace element selenium mitigates methamphetamine-induced neurotoxicity. Selenium can also alter DA production and turnover. However, studies have not directly addressed the role of selenium in DA neurotransmission. Selenoprotein P (SELENOP1) requires selenium for synthesis and transports selenium to the brain, in addition to performing other functions. We investigated whether SELENOP1 directly impacts (1) DA signaling and (2) the dopaminergic response to methamphetamine. We used fast-scan cyclic voltammetry to investigate DA transmission and the response to methamphetamine in NAc slices from C57/BL6J SELENOP1 KO mice. Recordings from SELENOP1 KO mouse slices revealed reduced levels of evoked DA release and slower DA uptake rates. Methamphetamine caused a dramatic increase in vesicular DA release in SELENOP1 KO mice not observed in wild-type controls. This elevated response was attenuated by SELENOP1 application through a selenium-independent mechanism involving SELENOP1-apolipoprotein E receptor 2 (ApoER2) interaction to promote dopamine D2 receptor (D2R) function. In wild-type mice, increased vesicular DA release in response to methamphetamine was revealed by blocking D2R activation, indicating that the receptor suppresses the methamphetamine-induced vesicular increase. Our data provide evidence of a direct physiological role for SELENOP1 in the dopaminergic response to methamphetamine and suggest a signaling role for the protein in DA transmission.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.