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Control of long-term synaptic plasticity by transsynaptic cell adhesion molecules

突触细胞粘附分子对长期突触可塑性的控制

基本信息

批准号：
318932082
负责人：
Dr. Xiaoting Wu
金额：
--
依托单位：
Nancy Friend Pritzker Laboratory
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/318932082?language=en
关键词：
Control long term synaptic plasticity

项目摘要

Long-term potentiation (LTP) is a phenomenon of synapse strengthening caused by recent neuronal activity patterns, which results in an increase of transmission between two neurons. It is accepted as one of the key processes underlying synaptic plasticity that is crucial for learning and memory. Despite the many studies on long-term synaptic plasticity during the past half century, the fundamental mechanisms that mediate LTP remain largely unknown, and the biological significance of LTP is incompletely understood. Recent advances in the field have uncovered an unexpected role of synaptic cell adhesion molecules in LTP. While their very name primarily evokes a mechanical function, synaptic cell adhesion molecules were discovered to mediate bidirectional signalling and contribute to the specification of pre- and postsynaptic properties. Therefore the present project is guided by the hypothesis that these neuronal cell adhesion molecules may mediate trans-synaptic signalling, which may explain and uncover some of the unknown molecular mechanisms in LTP. The project will focus on Leucine-rich repeat transmembrane proteins (LRRTMs), postsynaptic cell-adhesion ligands, which role in the synapses has just begun to be explored. I will address four main points to elucidate the role of LRRTMs in LTP. First, I will describe the fundamental role of LRRTMs in LTP in conditional knock-out mice. Second, I will search for molecular interactions of LRRTMs with effector proteins to identify potential LTP-relevant signalling pathways. Third, I will test the significance of these signalling pathways in vivo. Finally, I will examine the effect of hippocampal LRRTM manipulations on spatial learning to determine more specifically the role of LTP in memory. This project will pursue hypotheses that are novel, and if proven correct, will stimulate work in an entirely new area of neuronal cell biology. The notion that postsynaptic LTP requires enabling by trans-synaptic cell-adhesion molecules represents a fundamental conceptual innovation in the LTP field in which a potential presynaptic contribution to LTP traditionally is ruled out and therefore has broad implications for work in many areas of molecular, cellular, and behavioural neuroscience. This topic also has great potential for advancing understanding of the pathophysiology of mental illnesses given the genetic association between LRRTMs and disorders such as schizophrenia, and autism-associated disorders.

长时程增强（Long-term potentiation，LTP）是由神经元近期活动模式引起的突触增强现象，其结果是两个神经元之间的信息传递增加。它被认为是突触可塑性的关键过程之一，对学习和记忆至关重要。尽管在过去的半个世纪中对长时程突触可塑性进行了大量的研究，但其介导LTP的基本机制仍不清楚，LTP的生物学意义也不完全清楚。该领域的最新进展揭示了突触细胞粘附分子在LTP中的意想不到的作用。虽然它们的名字主要引起机械功能，但突触细胞粘附分子被发现介导双向信号传导并有助于突触前和突触后特性的规范。因此，本项目的指导下的假设，这些神经元细胞粘附分子可能介导的跨突触信号，这可能会解释和揭示一些未知的分子机制在LTP。该项目将集中于富含亮氨酸的重复跨膜蛋白（LRRTMs），突触后细胞粘附配体，其在突触中的作用刚刚开始探索。我将从四个方面阐述LRRTM在LTP中的作用。首先，我将描述LRRTM在条件性基因敲除小鼠LTP中的基本作用。其次，我将寻找LRRTM与效应蛋白的分子相互作用，以确定潜在的LTP相关的信号通路。第三，我将测试这些信号通路在体内的意义。最后，我将研究海马LRRTM操作对空间学习的影响，以更具体地确定LTP在记忆中的作用。这个项目将追求新的假设，如果被证明是正确的，将刺激神经细胞生物学的一个全新领域的工作。突触后LTP需要跨突触细胞粘附分子的支持，这一概念代表了LTP领域的一个基本概念创新，传统上排除了潜在的突触前对LTP的贡献，因此对分子，细胞和行为神经科学的许多领域的工作具有广泛的影响。鉴于LRRTM与精神分裂症和孤独症相关疾病等疾病之间的遗传关联，这一主题也有很大的潜力，以促进对精神疾病病理生理学的理解。