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Molecular mechanism of the synapse formation by neuronal activity

神经元活动形成突触的分子机制

基本信息

批准号：
15300130
负责人：
YAMAGATA Kanato
金额：
$ 10.69万
依托单位：
Tokyo Metropolitan Organization for Medical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

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

神经活动如何重塑突触？我们之前报道过一种名为Arcadlin的新型原钙粘蛋白，它是由神经活动在大脑中强烈诱导的。在这里，我们发现这种原钙粘蛋白 Arcadlin 通过调节 N-钙粘蛋白参与脊柱膜的重塑，而 N-钙粘蛋白在突触形成中起着至关重要的作用。 Arcadlin 合成由神经刺激诱导，并被转运至突触膜，与 N-钙粘蛋白结合。过度表达的Arcadlin原钙粘蛋白驱动N-钙粘蛋白进入核内体并抑制树突状丝状伪足和棘的生成。一致地，Arcadlin/PAPC 纯合突变小鼠的神经元比野生型神经元形成更多数量的突触点。在我们研究使用 Arcadlin 激活 N-钙粘蛋白内吞作用的细胞内信号传导机制期间，我们发现了 TAO2 激酶 (TAO2β) 的一种新型剪接形式，作为 Arcadlin 原钙粘蛋白的细胞内结合伴侣。细胞表面的 Arcadlin 的同亲相互作用通过激活 TAO2β 来激活 p38 MAPK。反过来，活性 p38 MAPK 反馈 TAO2β，在特定的丝氨酸处磷酸化其羧基末端结构域。这会触发 HEK293T 细胞和海马神经元中 N-cadherin/Arcadlin/TAO2β 复合物的共内吞作用。我们提出，这种新的信号转导途径调节的内吞作用涉及原钙粘蛋白、与其胞内结构域结合的 MAPKKK、MAPK 和经典钙粘蛋白，调节棘膜的粘附性和形态，导致神经活动诱导的突触强度发生变化。未来，研究 Arcadlin 原钙粘蛋白突变小鼠的行为和记忆将会很有趣。突触周围区域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 诱导的内吞作用可能提供粘附机制的调节与神经递质受体的插入/去除之间可能的关系。较少的