Molecular mechanism of the synapse formation by neuronal activity

神经活动如何重塑突触？我们以前报道了一种新的原钙粘蛋白命名为Arcadlin强烈诱导大脑中的神经活动。在这里，我们表明，这种原钙粘蛋白Arcadlin参与重建的棘膜，通过调节N-钙粘蛋白，在突触形成中发挥至关重要的作用。Arcadlin合成由神经刺激诱导，并被转运至突触膜，在那里它与N-钙粘蛋白结合。过表达的Arcadlin原钙粘蛋白驱动N-钙粘蛋白进入内体并抑制树突丝状伪足和棘的产生。一致地，来自Arcadlin/PAPC纯合突变小鼠的神经元形成比野生型神经元更多的突触点。在我们对激活N-钙粘蛋白与Arcadlin的内吞作用的细胞内信号传导机制的研究中，我们鉴定了TAO 2激酶（TAO 2 β）的新剪接形式作为Arcadlin原钙粘蛋白的细胞内结合伴侣。嗜同性相互作用 ...更多信息 细胞表面的Arcadlin通过激活TAO 2 β激活p38 MAPK。反过来，活性p38 MAPK反馈TAO 2 β，使其羧基末端结构域在特定丝氨酸处磷酸化。这触发了HEK 293 T细胞和海马神经元中N-钙粘蛋白/Arcadlin/TAO 2 β复合物的共内吞。我们建议，这种新的信号转导途径涉及原钙粘蛋白，MAPKKK，结合到其胞内结构域，MAPK和经典的钙粘蛋白调节的内吞作用调节棘膜的形态和结构，导致神经活动诱导的突触强度的变化。研究Arcadlin原钙粘蛋白突变小鼠的行为和记忆功能是今后的研究方向。在突触周围区域的突触棘膜的粘附装置现在可以被认为是剧烈重塑的焦点。p38 MAPK诱导的内吞作用的参与可能提供了一个可能的关系之间的调节粘附机制和插入/删除的神经递质受体。少

How does neural activity remodel synapses? We previously reported a novel protocadherin designated Arcadlin was strongly induced in the brain by neural activity. Here, we show that this protocadherin Arcadlin is involved in the remodeling of spine membrane by regulating N-cadherin that that play a crucial role in synapse formation. Arcadlin synthesis is induced by neural stimulation and it is transported to the synaptic membrane, where it binds to N-cadherin. Overexpressed Arcadlin protocadherin drives N-cadherin into endosomes and suppresses the generation of dendritic filopodia and spines. Consistently, neurons from Arcadlin/PAPC homozygous mutant mice form a larger number of synaptic puncta than wild-type neurons. During our investigations into the intracellular signaling mechanism that activates the endocytosis of N-cadherin with Arcadlin, we identified a novel splice form of TAO2 kinase (TAO2β) as an intracellular binding partner of the Arcadlin protocadherin. Homophilic interacti … More on of Arcadlin on cell surface activates p38 MAPK through the activation of TAO2β. In turn, active p38 MAPK feeds back on TAO2β, phosphorylating its carboxy-terminal domain at a specific Serine. This triggers the co-endocytosis of N-cadherin/Arcadlin/TAO2β complex in HEK293T cells and hippocampal neurons. We propose that endocytosis regulated by this novel signal transduction pathway involving a protocadherin, a MAPKKK that binds to its intracellular domain, a MAPK and a classical cadherin modulates the adhesiveness and morphology of spine membranes, resulting in changes in synaptic strength induced by neural activity. In the future, it will be interesting to investigate behavior and memory in mice mutant for the Arcadlin protocadherin. The adhesive apparatus of synaptic spine membranes in the peri-synaptic region can now be recognized as a focal point of vigorous remodeling. Involvement of p38 MAPK-induced endocytosis may provide a possible relationship between the modulation of adhesive machinery and the insertion/removal of neurotransmitter receptors. Less