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

长时程增强(LTP)是一种由最近的神经元活动模式引起的突触强化现象，导致两个神经元之间的传递增加。它被认为是突触可塑性的关键过程之一，突触可塑性对学习和记忆至关重要。尽管在过去的半个世纪里，人们对长时突触的可塑性进行了大量的研究，但其调节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黏附分子在LTP中意想不到的作用。虽然它们的名字主要唤起一种机械功能，但突触细胞黏附分子被发现介导双向信号传递，并有助于指定突触前和突触后的特性。因此，本项目以这些神经细胞黏附分子可能介导跨突触信号的假设为指导，这可能解释和揭示LTP中一些未知的分子机制。该项目将把重点放在富含亮氨酸的重复跨膜蛋白(LRRTM)上，这是突触后细胞黏附配体，它在突触中的作用刚刚开始探索。我将讨论四个要点，以阐明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LRRTMS与效应蛋白的分子相互作用，以确定潜在的LTP相关信号通路。第三，我将在体内测试这些信号通路的意义。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。这个项目将追求新颖的假设，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需要跨突触细胞黏附分子启动的概念代表了LTP领域的一项根本性概念创新，传统上排除了突触前对LTP的潜在贡献，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意义。鉴于LRRTM与精神分裂症和自闭症相关障碍等疾病之间的遗传关联，这一主题也具有促进对精神疾病病理生理学的理解的巨大潜力。

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.