Lead Exposure during Synaptogenesis Alters Vesicular Proteins and Impairs Vesicular Release: Potential Role of NMDA Receptor-Dependent BDNF Signaling
Lead Exposure during Synaptogenesis Alters Vesicular Proteins and Impairs Vesicular Release: Potential Role of NMDA Receptor-Dependent BDNF Signaling
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DOI：
10.1093/toxsci/kfq111
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发表时间：
2010-07-01
影响因子：
3.8
通讯作者：
Guilarte, Tomas R.
中科院分区：
文献类型：
--
作者：
Neal, April P.;Stansfield, Kirstie H.;Guilarte, Tomas R.
已知铅（Pb 2+）暴露会影响Vim和细胞培养模型中突触前神经递质的释放。然而，Pb 2+损害神经递质释放的确切机制仍然未知。在目前的研究中，我们表明，在培养的海马神经元的突触发生过程中，铅+暴露产生的损失突触素（Syn）和小突触泡蛋白（Syb），两种蛋白质参与囊泡释放。铅暴露也增加了突触前接触部位的数量。然而，这些推定的突触前接触位点中的许多缺乏参与囊泡胞吐的可溶性NSF附着蛋白受体复合物蛋白。使用FM 1-43染料对囊泡释放的分析证实，Pb 2+暴露损害囊泡释放并减少快速释放位点的数量。由于Pb 2+是一种有效的N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，我们测试了NMDAR抑制可能产生突触前效应的假设。我们发现，NMDAR抑制氨基膦酸戊酸模仿突触前铅暴露的影响。NMDAR活性与跨突触神经营养因子脑源性神经营养因子（BDNF）的信号传导有关，并且我们观察到，在Pb 2+暴露的同一时期，proBDNF的细胞表达和BDNF的释放都降低。此外，外源性添加BDNF拯救了Pb 2+的突触前效应。我们认为，突触前缺陷导致的铅暴露在突触发生过程中介导的破坏NMDAR依赖的BDNF信号。
Lead (Pb2+) exposure is known to affect presynaptic neurotransmitter release in both in vim and cell culture models. However, the precise mechanism by which Pb2+ impairs neurotransmitter release remains unknown. In the current study, we show that Pb2+ exposure during synaptogenesis in cultured hippocampal neurons produces the loss of synaptophysin (Syn) and synaptobrevin (Syb), two proteins involved in vesicular release. Pb2+ exposure also increased the number of presynaptic contact sites. However, many of these putative presynaptic contact sites lack Soluble NSF attachment protein receptor complex proteins involved in vesicular exocytosis. Analysis of vesicular release using FM 1-43 dye confirmed that Pb2+ exposure impaired vesicular release and reduced the number of fast-releasing sites. Because Pb2+ is a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, we tested the hypothesis that NMDAR inhibition may be producing the presynaptic effects. We show that NMDAR inhibition by aminophosphonovaleric acid mimics the presynaptic effects of Pb2+ exposure. NMDAR activity has been linked to the signaling of the transsynaptic neurotrophin brain-derived neurotrophic factor (BDNF), and we observed that both the cellular expression of proBDNF and release of BDNF were decreased during the same period of Pb2+ exposure. Furthermore, exogenous addition of BDNF rescued the presynaptic effects of Pb2+. We suggest that the presynaptic deficits resulting from Pb2+ exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling.