High dose zinc supplementation induces hippocampal zinc deficiency and memory impairment with inhibition of BDNF signaling.
High dose zinc supplementation induces hippocampal zinc deficiency and memory impairment with inhibition of BDNF signaling.
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DOI：
10.1371/journal.pone.0055384
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liu R
中科院分区：
文献类型：
--
作者：
Yang Y;Jing XP;Zhang SP;Gu RX;Tang FX;Wang XL;Xiong Y;Qiu M;Sun XY;Ke D;Wang JZ;Liu R
锌离子在海马高度富集，在调节空间学习记忆中起着关键作用。当膳食强化和补锌增加了锌的摄入量，特别是在青年人中，过量锌对脑功能的毒性被低估了。本研究以15 ppm锌（低剂量）、60 ppm锌（高剂量）和正常饮水喂养ICR小鼠3个月，观察其行为学和脑锌稳态的变化。高剂量锌组小鼠出现海马依赖性记忆障碍。出乎意料的是，在海马中观察到锌缺乏，而不是锌过载，特别是在苔藓纤维-CA 3锥体突触中。海马区学习记忆相关受体和突触蛋白如NMDA-NR 2A、NR 2B、AMPA-GluR 1、PSD-93和PSD-95的表达水平明显降低，树突棘明显缺失。与这些发现一致，高剂量锌摄入导致海马BDNF水平和TrkB神经营养信号转导降低。最后，通过脑锌注射直接增加脑锌水平诱导BDNF表达，体内锌螯合可逆转BDNF表达。这些结果表明，锌在海马依赖性学习记忆和BDNF表达中起重要作用，高剂量补充锌可诱导海马特异性锌缺乏，并通过降低突触锌的利用率和减少BDNF的表达而进一步损害学习记忆。
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.