Involvement of the synapse‐specific zinc transporter ZnT3 in cadmium‐induced hippocampal neurotoxicity

Abstract

The present study examined the involvement of zinc (Zn)‐transporters (ZnT3) in cadmium (Cd)‐induced alterations of Zn homeostasis in rat hippocampal neurons. We treated primary rat hippocampal neurons for 24 or 48 hr with various concentrations of CdCl2 (0, 0.5, 5, 10, 25, or 50 μM) and/or ZnCl 2 (0, 10, 30, 50, 70, or 90 μM), using normal neuronal medium as control. By The CellTiter 96 ® Aqueous One Solution Cell Proliferation Assay (MTS; Promega, Madison, WI) assay and immunohistochemistry for cell death markers, 10 and 25 μM of Cd were found to be noncytotoxic doses, and both 30 and 90 μM of Zn as the best concentrations for cell proliferation. We tested these selected doses. Cd, at concentrations of 10 or 25 μM (and depending on the absence or presence of Zn), decreased the percentage of surviving cells. Cd‐induced neuronal death was either apoptotic or necrotic depending on dose, as indicated by 7‐AAD and/or annexin V labeling. At the molecular level, Cd exposure induced a decrease in hippocampal brain‐derived neurotrophic factor‐tropomyosin receptor kinase B (BDNF‐TrkB) and Erk1/2 signaling, a significant downregulation of the expression of learning‐ and memory‐related receptors and synaptic proteins such as the NMDAR NR2A subunit and PSD‐95, as well as the expression of the synapse‐specific vesicular Zn transporter ZnT3 in cultured hippocampal neurons. Zn supplementation, especially at the 30 μM concentration, led to partial or total protection against Cd neurotoxicity both with respect to the number of apoptotic cells and the expression of several genes. Interestingly, after knockdown of ZnT3 by small interfering RNA transfection, we did not find the restoration of the expression of this gene following Zn supplementation at 30 μM concentration. These data indicate the involvement of ZnT3 in the mechanism of Cd‐induced hippocampal neurotoxicity.

Reactivity of Thiol-Rich Zn Sites in Diacylglycerol-Sensing PKC C1 Domain Probed by NMR Spectroscopy

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Adolescent cadmium exposure impairs cognition and hippocampal neurogenesis in C57BL/6 mice

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“…The numerical value of the control group was calculated by subtracting the OD value of the blank group from the OD value of the control group. The calculation result of the experimental group was divided by the calculation result of the control group, and finally multiplied by 100 (34).…”