蛋白激酶D1调控神经型钙粘素N-cadherin促进突触发育和学习记忆的机制研究

项目名称： 蛋白激酶D1调控神经型钙粘素N-cadherin促进突触发育和学习记忆的机制研究

项目编号： No.81600989

项目类型： 青年科学基金项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 岑程

作者单位： 北京大学

项目金额： 17万元

中文摘要： 神经系统中，突触的形态功能和突触可塑性对神经环路和大脑高级功能至关重要，并在阿尔兹海默症等疾病的发生中起到关键作用。我们的前期工作揭示，海马神经元发育晚期，蛋白激酶D1（PKD1）通过增加神经型钙粘素N-cadherin（N-cad）的膜定位促进树突棘发育和突触功能，该过程依赖于PKD1的激酶活性和其在高尔基体上的定位。在体研究表明，海马脑区阻断PKD1与N-cad的相互作用使动物学习记忆能力提升。据此我们提出假说：神经元发育晚期至成熟阶段，干扰PKD1与N-cad的相互作用促进非特异性突触连接的消退，增强成熟突触的比例和功能，提高动物学习记忆能力。围绕该假说，我们将明确生理与病理状态下PKD1与N-cad的相互作用对学习记忆各阶段的影响，以及对突触形态和功能的调控机制。该研究对阐明调控学习记忆和突触重塑二者关系的分子机制具有重要意义，并为临床上神经系统疾病的诊断和治疗提供新的靶点和思路。

中文关键词： 神经发育；突触可塑性；细胞粘附分子；树突棘修剪；学习记忆

英文摘要： Functional synapse formation, maturation and remodeling are essential for the wiring of neural circuits in developing brain and have been implied to play important roles in the emergence of Alzheimer's disease. Our previous studies demonstrate that in the late phase of neuronal development, PKD1 interacts with N-cadherin and promotes synapse formation and function depending on its kinase activity and its Golgi localization. Notably, in vivo disrupting the interactions of PKD1 and N-cadherin leads to a reduction in dendritic spines but an improvement of the proportion of mushroom spines and spatial learning and memory. Based on the above results and literature, we hypothesize that disrupting the binding of PKD1 and N-cadherin accelerates spine maturation while decreases the unspecific synapses. This process promotes the effect of information storage, leading to improved learning and memory of rats in the water maze test. To prove this hypothesis, we will first determine the effects of PKD1 and N-cadherin in different stages of learning and memory, and explore the underlying molecular mechanisms of animal behaviors associated with synaptic plasticity and remodeling. We will also demonstrate the function of PKD1 in pathological states of AD transgenic mice. Our project will shed insight into the important roles of PKD1 in learning and memory and provide new targets in clinical treatment of neurological diseases.

英文关键词： neural development;synaptic plasticity;adhesion molecule;spine pruning;learning and memory