Macroglia-derived thrombospondin 2 regulates alterations of presynaptic proteins of retinal neurons following elevated hydrostatic pressure.
Macroglia-derived thrombospondin 2 regulates alterations of presynaptic proteins of retinal neurons following elevated hydrostatic pressure.
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大胶质细胞衍生的血小板反应蛋白 2 调节静水压升高后视网膜神经元突触前蛋白的变化
DOI：
10.1371/journal.pone.0185388
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Chen D
中科院分区：
文献类型：
--
作者：
Wang S;Hu T;Wang Z;Li N;Zhou L;Liao L;Wang M;Liao L;Wang H;Zeng L;Fan C;Zhou H;Xiong K;Huang J;Chen D
许多关于高眼压后视网膜损伤和修复的研究表明，通过各种措施可以提高视网膜神经元的存活率。然而，视觉功能的恢复远低于预期。视觉信号通路中视网膜突触的稳态是视觉信号传递的关键结构基础。我们前期的研究发现，大鼠视网膜神经元间突触结构的复杂变化发生的时间远早于视网膜神经节细胞的明显变性。在抢救策略中缺乏对这些早期视网膜突触变化的考虑可能是眼内压升高后使用的视网膜神经元保护方法类型导致视功能恢复有限的部分原因。因此，研究高眼压损伤后突触变化的调控机制，可能为视功能的挽救提供新的思路。本研究发现，在中枢神经系统发育中突触发生的重要调节因子血小板反应蛋白2分布于视网膜大胶质细胞，其受体α2δ-1分布于视网膜神经元。将包括混合的视网膜大胶质细胞/神经元培养物和视网膜神经元培养物的细胞培养物暴露于升高的静水压力2小时。在混合培养条件下，随着静水压的升高，胶质细胞酸性蛋白（活化的大胶质细胞的标志物）、血小板反应蛋白2、α2δ-1和突触前蛋白的表达水平增加，而突触后蛋白的表达水平无明显变化。靶向血小板反应蛋白2的SiRNA可以减少静水压力升高引起的突触前蛋白的上调。然而，在视网膜神经元培养，静水压力升高并不影响突触前或突触后蛋白的表达。相反，添加重组血小板反应蛋白2蛋白的视网膜神经元培养物上调了突触前蛋白的水平。最后，加巴喷丁通过阻断血小板反应蛋白2和α2δ-1的相互作用降低混合培养物中突触前蛋白的表达。总之，这些结果表明，激活的大胶质细胞可能参与了视网膜神经元在静水压力升高后突触前蛋白的改变，并且大胶质细胞衍生的血小板反应蛋白2可能通过与其神经元受体α2δ-1结合来调节这些变化。
Many studies on retinal injury and repair following elevated intraocular pressure suggest that the survival ratio of retinal neurons has been improved by various measures. However, the visual function recovery is far lower than expected. The homeostasis of retinal synapses in the visual signal pathway is the key structural basis for the delivery of visual signals. Our previous studies found that complicated changes in the synaptic structure between retinal neurons occurred much earlier than obvious degeneration of retinal ganglion cells in rat retinae. The lack of consideration of these earlier retinal synaptic changes in the rescue strategy may be partly responsible for the limited visual function recovery with the types of protective methods for retinal neurons used following elevated intraocular pressure. Thus, research on the modulatory mechanisms of the synaptic changes after elevated intraocular pressure injury may give new light to visual function rescue. In this study, we found that thrombospondin 2, an important regulator of synaptogenesis in central nervous system development, was distributed in retinal macroglia cells, and its receptor α2δ-1 was in retinal neurons. Cell cultures including mixed retinal macroglia cells/neuron cultures and retinal neuron cultures were exposed to elevated hydrostatic pressure for 2 h. The expression levels of glial fibrillary acidic protein (the marker of activated macroglia cells), thrombospondin 2, α2δ-1 and presynaptic proteins were increased following elevated hydrostatic pressure in mixed cultures, but the expression levels of postsynaptic proteins were not changed. SiRNA targeting thrombospondin 2 could decrease the upregulation of presynaptic proteins induced by the elevated hydrostatic pressure. However, in retinal neuron cultures, elevated hydrostatic pressure did not affect the expression of presynaptic or postsynaptic proteins. Rather, the retinal neuron cultures with added recombinant thrombospondin 2 protein upregulated the level of presynaptic proteins. Finally, gabapentin decreased the expression of presynaptic proteins in mixed cultures by blocking the interaction of thrombospondin 2 and α2δ-1. Taken together, these results indicate that activated macroglia cells may participate in alterations of presynaptic proteins of retinal neurons following elevated hydrostatic pressure, and macroglia-derived thrombospondin 2 may modulate these changes via binding to its neuronal receptor α2δ-1.
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影响因子：
4.4
作者：
Bachleda AR;Pevny LH;Weiss ER
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