Presenilin Regulates Retinotectal Synapse Formation through EphB2 Receptor Processing.
Presenilin Regulates Retinotectal Synapse Formation through EphB2 Receptor Processing.
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DOI：
10.1002/dneu.22638
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发表时间：
2018-12
影响因子：
3
通讯作者：
Pratt KG
中科院分区：
文献类型：
--
作者：
Liu Z;Thakar A;Santoro SW;Pratt KG
早老素（PS）作为γ-分泌酶的催化组分，通过切割淀粉样前体蛋白而与阿尔茨海默病（AD）发生发展密切相关。然而，PS/γ-分泌酶也切割在发育期间重要的多种单程跨膜蛋白，包括Notch、netrin受体DCC、钙粘蛋白、drebrin-A和EphB 2受体。由于转基因PS-KO小鼠不能存活至出生，因此已分别使用细胞培养物或条件性敲除小鼠在胚胎后期或出生后早期发育阶段对该分子进行了研究。因此，PS在突触形成中的功能尚未得到很好的解决。在这里，我们研究的作用，PS在发展中的非洲爪蟾蝌蚪retinotectal电路，在体内模型，允许蛋白质的表达，特别是在视网膜神经节细胞和顶盖神经元之间的突触形成的高峰期间进行操作。我们发现，抑制突触后顶盖神经元的PS损害蝌蚪的视觉回避行为。全细胞记录表明较弱的retinotectal突触传递，其特征在于显着减少NMDA受体（NMDAR）和AMPA受体（AMPAR）介导的电流。我们还发现EphB 2受体的C-尾片段的表达挽救了降低的NMDAR介导的应答，所述C-尾片段通常被PS/γ-分泌酶切割并且已经显示在突触处上调NMDAR。我们的数据确定正常PS功能对于通过切割EphB 2受体来正确形成和加强视网膜顶盖突触是重要的。
As the catalytic component of γ-secretase, presenilin (PS) has long been studied in the context of Alzheimer’s disease through cleaving the amyloid precursor protein. PS/γ-secretase, however, also cleaves a multitude of single-pass transmembrane proteins that are important during development, including Notch, the netrin receptor DCC, cadherins, drebrin-A, and the EphB2 receptor. Because transgenic PS-KO mice do not survive to birth, studies of this molecule during later embryonic or early postnatal stages of development have been carried out using cell cultures or conditional knock-out mice, respectively. As a result, the function of PS in synapse formation had not been well-addressed. Here we study the role of PS in the developing Xenopus tadpole retinotectal circuit, an in-vivo model that allows for protein expression to be manipulated specifically during the peak of synapse formation between retinal ganglion cells and tectal neurons. We found that inhibiting PS in the postsynaptic tectal neurons impaired tadpole visual avoidance behavior. Whole cell recordings indicated weaker retinotectal synaptic transmission which was characterized by significant reductions in both NMDA receptor (NMDAR)- and AMPA receptor (AMPAR)-mediated currents. We also found that expression of the C-tail fragment of the EphB2 receptor, which is normally cleaved by PS/γ-secretase and which has been shown to upregulate NMDARs at the synapse, rescued the reduced NMDAR-mediated responses. Our data determine that normal PS function is important for proper formation and strengthening of retinotectal synapses through cleaving the EphB2 receptor.
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影响因子：
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作者：
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影响因子：
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影响因子：
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作者：
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