title: High dose zinc supplementation induces hippocampal zinc deficiency and memory impairment with inhibition of BDNF signaling.
abstract: Zinc ions highly concentrate in hippocampus and play a key role in modulating spatial learning and memory. At a time when dietary fortification and supplementation of zinc have increased the zinc consuming level especially in the youth, the toxicity of zinc overdose on brain function was underestimated. In the present study, weaning ICR mice were given water supplemented with 15 ppm Zn (low dose), 60 ppm Zn (high dose) or normal lab water for 3 months, the behavior and brain zinc homeostasis were tested. Mice fed high dose of zinc showed hippocampus-dependent memory impairment. Unexpectedly, zinc deficiency, but not zinc overload was observed in hippocampus, especially in the mossy fiber-CA3 pyramid synapse. The expression levels of learning and memory related receptors and synaptic proteins such as NMDA-NR2A, NR2B, AMPA-GluR1, PSD-93 and PSD-95 were significantly decreased in hippocampus, with significant loss of dendritic spines. In keeping with these findings, high dose intake of zinc resulted in decreased hippocampal BDNF level and TrkB neurotrophic signaling. At last, increasing the brain zinc level directly by brain zinc injection induced BDNF expression, which was reversed by zinc chelating in vivo. These results indicate that zinc plays an important role in hippocampus-dependent learning and memory and BDNF expression, high dose supplementation of zinc induces specific zinc deficiency in hippocampus, which further impair learning and memory due to decreased availability of synaptic zinc and BDNF deficit.
authors: Key Laboratory of Neurological Disease, Ministry of Education, China.
authors: Yang
authors: Y
authors: Yang
authors: Xiao-Peng
authors: XP
authors: Jing
authors: Shou-Peng
authors: SP
authors: Zhang
authors: Run-Xia
authors: RX
authors: Gu
authors: Fang-Xu
authors: FX
authors: Tang
authors: Xiu-Lian
authors: XL
authors: Wang
authors: Yan
authors: Y
authors: Xiong
authors: Mei
authors: M
authors: Qiu
authors: Xu-Ying
authors: XY
authors: Sun
authors: Dan
authors: D
authors: Ke
authors: Jian-Zhi
authors: JZ
authors: Wang
authors: Rong
authors: R
authors: Liu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D019587:Dietary Supplements; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D006652:Histological Techniques; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008569:Memory Disorders / Q000139:chemically induced*; D051379:Mice; D008813:Mice, Inbred ICR; D020813:Receptor, trkB / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015032:Zinc / Q000008:administration & dosage / Q000172:deficiency* / Q000633:toxicity*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D020813:Receptor, trkB; C501445:Dlg2 protein, mouse; D051528:Guanylate Kinases; D015032:Zinc
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