Dysregulation of BDNF-TrkB Signaling in Developing Hippocampal Neurons by Pb2+: Implications for an Environmental Basis of Neurodevelopmental Disorders
Dysregulation of BDNF-TrkB Signaling in Developing Hippocampal Neurons by Pb2+: Implications for an Environmental Basis of Neurodevelopmental Disorders
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DOI：
10.1093/toxsci/kfs090
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发表时间：
2012-05-01
影响因子：
3.8
通讯作者：
Guilarte, Tomas R.
中科院分区：
文献类型：
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作者：
Stansfield, Kirstie H.;Pilsner, J. Richard;Guilarte, Tomas R.
突触发育和功能的失调与神经退行性疾病和精神疾病的病理生理学有关。在神经元和突触发育中具有重要功能的神经营养因子是脑源性神经营养因子（BDNF）。在本文中，我们研究了胚胎大鼠海马神经元突触发生期间铅（Pb 2+）暴露对脑源性神经营养因子原肌球蛋白相关激酶B（Trk B）信号传导的影响。我们发现，Pb 2+暴露降低BDNF基因和蛋白质的表达，它也可能改变运输的BDNF囊泡的网站的释放，通过改变亨廷顿蛋白磷酸化和蛋白质水平。Pb 2+对BDNF基因表达的影响与钙敏感性外显子IV转录水平的特异性降低以及转录抑制因子甲基-CpG结合蛋白（MeCP 2）的磷酸化和蛋白表达降低有关。TrkB蛋白水平和酪氨酸816处的自磷酸化显著降低，Pb 2+暴露伴随着p75神经营养因子受体（p75（NTR））水平的增加和TrkB-p75（NTR）共定位的改变。最后，突触蛋白1的磷酸化，突触前的BDNF-TrkB信号的目标，显着降低铅2+暴露与总突触蛋白I蛋白水平没有影响。Pb 2+暴露对突触蛋白I磷酸化的这种影响可能有助于解释我们先前记录的囊泡释放的损伤（Neal，A. P.的人，Stansfield，K. H、Worley，P. E，Thompson，R. E、和Guilarte，T. R.（2010年）。突触发生过程中铅暴露改变囊泡蛋白并损害囊泡释放：N-甲基-D-天冬氨酸受体（NMDAR）依赖的BDNF信号传导的潜在作用。毒理学. Sci. 116，249-263），因为它控制囊泡从储备池到容易释放池的运动。总之，本研究表明，在培养的海马神经元的突触发生期间，Pb 2+暴露破坏了由BDNF-TrkB信号转导调节的多个突触过程，对突触功能和神经元发育具有长期影响。
Dysregulation of synaptic development and function has been implicated in the pathophysiology of neurodegenerative disorders and mental disease. A neurotrophin that has an important function in neuronal and synaptic development is brain-derived neurotrophic factor (BDNF). In this communication, we examined the effects of lead (Pb2+) exposure on BDNF-tropomyosin-related kinase B (TrkB) signaling during the period of synaptogenesis in cultured neurons derived from embryonic rat hippocampi. We show that Pb2+ exposure decreases BDNF gene and protein expression, and it may also alter the transport of BDNF vesicles to sites of release by altering Huntingtin phosphorylation and protein levels. Combined, these effects of Pb2+ resulted in decreased concentrations of extracellular mature BDNE The effect of Pb2+ on BDNF gene expression was associated with a specific decrease in calcium-sensitive exon IV transcript levels and reduced phosphorylation and protein expression of the transcriptional repressor methyl-CpG-binding protein (MeCP2). TrkB protein levels and autophosphorylation at tyrosine 816 were significantly decreased by Pb2+ exposure with a concomitant increase in p75 neurotrophin receptor (p75(NTR)) levels and altered TrkB-p75(NTR) colocalization. Finally, phosphorylation of Synapsin 1, a presynaptic target of BDNF-TrkB signaling, was significantly decreased by Pb2+ exposure with no effect on total Synapsin I protein levels. This effect of Pb2+ exposure on Synapsin I phosphorylation may help explain the impairment in vesicular release documented by us previously (Neal, A. P., Stansfield, K. H., Worley, P. E, Thompson, R. E., and Guilarte, T. R. (2010). Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of N-Methyl-D-aspartate receptor (NMDAR) dependent BDNF signaling. Toxicol. Sci. 116, 249-263) because it controls vesicle movement from the reserve pool to the readily releasable pool. In summary, the present study demonstrates that Pb2+ exposure during the period of synaptogenesis of hippocampal neurons in culture disrupts multiple synaptic processes regulated by BDNF-TrkB signaling with long-term consequences for synaptic function and neuronal development.