High Dose Supplementation Of Zinc Induces Hippocampal Zinc Deficiency And Memory Impairment With Involvement Of BDNF Deficit

Background: Zinc ions highly concentrate in hippocampus and play a key role inmodulating spatial learning and memory. It was reported that zinc supplemented ratsshowed spatial reference memory deficit, however, the detailed mechanisms underlyingthe memory impairment need further exploration.Methods: Weaning ICR mice were given water supplemented with15ppm Zn (lowdose),60ppm Zn (high dose) or normal lab water for3months, then a series ofbehavioral tests (such as T-maze test, contextual discrimination,contextual fearconditioning and open field test) were used to detect the abilities of learning andmemory. After the behaviour test, zinc concentrations in the blood and brain weredetected by atomic absorption spectrophotometry. The chelatable zinc (synapticreleasable zinc) was detected by Timm staining and TSQ staining, and the protein levelsof memory-related glutamate receptors and scaffolding proteins were detected bywestern blotting. To further confirm the relationship between zinc and BDNF, weinjected zinc sulfate into the rat brains, with or without intraperitonea l injection of zinc chelator CQ, then detected the protein levels of BDNF by western blotting.Results:⑴Mice fed high dose of zinc showed hippocampus-dependent memoryimpairment;⑵High dose supplementation of zinc induce hippocampal zinc deficiency,especially in the mossy fiber-CA3pyramid synapse;⑶The expression levels oflearning and memory related receptors and synaptic proteins such as NMDA-NR2A,NR2B, AMPA-GluR1, GluR2, PSD93and PSD95were significantly decreased inhippocampus of high dose zinc supplemented mice, with significant loss of dendriticspines;⑷In keeping with these findings, high dose intake of zinc resulted in decreasedhippocampal BDNF level and TrkB neurotrophic signaling;⑸Increasing the brain zinclevel directly by brain zinc injection induced BDNF expression, which was reversed byzinc chelating in vivo.Conclusions: These results indicate that zinc plays an important role inhippocampus-dependent learning and memory and BDNF expression, high dosesupplementation of zinc induces specific zinc deficiency in hippocampus, which furtherimpair learning and memory due to decreased availab ility of synaptic zinc and BDNFdeficit.