Regulation of synaptogenesis and synaptic plasticity by cell adhesion molecules

中枢神经系统（CNS）每时每刻都在适应环境。这种适应是学习和记忆以及对滥用药物的依赖性和耐受性等各种现象的基础。神经网络的重构是中枢神经适应的基础，在本研究中，我们观察到连接神经纤维的突触接触的重构，从而形成复杂的神经网络。树突棘，突触后结构，接受兴奋性突触输入，可视化与异源表达的水母绿色荧光蛋白（GFP）在活的海马神经元。脊柱在没有人工刺激的情况下可快速往复运动。通过高K+细胞外溶液的膜去极化触发的突触刺激，棘变大多达30%。这导致参与化学神经传递的区域扩大，从而提高神经传递的效率。这种神经刺激的积累和由此产生的增大可能导致某个神经通路的增强，我们还研究了活动诱导突触重塑的分子机制：1）突触细胞粘附分子钙粘蛋白（Cadherin）的活性是脊髓增大所必需的。2)突触刺激增强N-钙粘蛋白活性。3)另一种突触细胞粘附分子，Arcadlin，抑制N-钙粘蛋白，并减少突触的数量。4)Arcadlin通过内吞作用驱动N-钙粘蛋白的内化。5)Arcadlin/N-cadherin的内吞信号转导通路涉及p38 MAP激酶。

Central nervous system (CNS) is adapting to the environment at every moment. The adaptation underlies various phenomena such as learning and memory, and dependence and tolerance to abused drugs. Remodeling of neural network is supposed to provide the basis of CNS adaptation.In this study, we have observed the remodeling of synaptic contacts that connects neural fibers resulting in complex neural networking. Dendritic spine, the postsynaptic structure that receives excitatory synaptic input, was visualized in living hippocampal neurons with a heterologously expressed jellyfish green fluorescent protein (GFP). Spine showed rapid reciprocal movement without an artificial stimulation. By synaptic stimulation triggered by membrane depolarization with high K+ extracellular solution, spine became enlarged as much as 30 %. This results in enlargement of the area involved in chemical neurotransmission, hence enhancing the efficiency of neurotransmission. Accumulation of such a neural stimulation and resultant enlargement may lead to the enhancement of a certain neural pathway.We have also investigated the molecular mechanism of the activity-induced synaptic remodeling : 1)Cadherin (a synaptic cell adhesion molecule) activity is required for the enlargement of spine. 2)Synaptic stimulation enhances N-cadherin activity. 3)Another synaptic cell adhesion molecule, Arcadlin, inhibits N-cadherin adhesiveness, and decreases the number of synapses. 4)Arcadlin drives internalization of N-cadherin by endocytosis. 5)The endocytic signal transduction pathway of Arcadlin/N-cadherin involves p38 MAP kinase.These results were submitted to a high quality scientific journal.