Investigation of Central Nervous System synaptogenesis

在神经发育过程中，神经元和它们的靶细胞之间必须形成精确的连接，才能使成熟的中枢神经系统正常运作。这个网络的连接与轴突引导密切相关。轴突必须长距离移动，并连接到它们的特定目标。突触的形成对中枢神经系统的发育、成熟和重塑也是至关重要的。查明它们的形成和稳定所涉及的机制仍然是一个根本问题。*几十年来，人们已经知道大麻类物质对学习和记忆有深远的影响。由于存在于胎儿和出生后早期，内源性产生的大麻素称为内源性大麻素(ECB)及其CB1受体(CB1Rs)被认为参与了一些发育事件，如增殖、分化、迁移、轴突引导和突触发生。*本研究计划的总体目标旨在确定ECB如何调节轴突引导和突触形成/稳定。由于篇幅所限，本文仅对研究突触形成/重塑的部分进行详细描述。*我们已经获得了体内和体外证据表明，大麻类化合物通过其CB1R减少突触数量。最近，我们发现在结直肠癌(DCC)中，ECB通过CB1R调节轴突导向，其机制涉及蛋白激酶A(PKA)和轴突导向受体缺失。有趣的是，在发育过程中指导轴突延伸的几个分子似乎也调节突触的形成。这些观察使我们研究了ECB及其CB1R调节突触形成和重塑的一种新功能。*拟议的研究计划旨在确定ECB和CB1R在突触形成/稳定中的贡献以及它们发挥作用的机制。我们的初步发现表明，我们已经确定了一种在调节突触数量方面发挥重要作用的新机制。研究这一点将有助于提高我们对调节神经元之间通信的基本机制的理解。结合药理学、转基因模型、分子生物学、免疫细胞化学、电子显微镜和电生理学来研究突触的发育和成熟，将提供一个创新的多学科训练环境。

During neural development, precise connections must form between neurons and their targets for the proper function of the mature Central Nervous System. The wiring of this network is strongly linked to axon guidance. Axons have to travel on long distance and connect to their specific targets. The formation of synapses is also crucial to development, maturation, and remodeling of the Central Nervous System (CNS). Identifying the mechanisms involved in their formation and stabilization remains a fundamental question. ******It has been known for decades that cannabinoids have a profound influence on learning and memory. Due to their presence at the foetal and early postnatal periods, endogenously produced cannabinoids called endocannabinoids (eCBs) and their CB1 receptors (CB1Rs) have been proposed to participate to several developmental events such as the proliferation, differentiation, migration, axon guidance, and synaptogenesis. ******The overall goal of this research program aims to determine how eCBs can modulate axon guidance and synapse formation/stabilization. Due to space limitations, only the part studying the synapse formation/remodeling will be described in details. ******We have obtained in vivo and in vitro evidence indicating that cannabinoids decrease synapse number via their CB1R. Recently, we showed that eCBs via CB1R modulate axon guidance by a mechanism implicating Protein Kinase A (PKA) and an axon guidance receptor called Deleted in Colorectal Cancer (DCC). Interestingly, several molecules that direct neurite extension during development also appear to regulate synapse formation. These observations led us to investigate a novel function for eCBs and their CB1R regulating the formation and the remodeling of synapses. ******The proposed research program aims to identify the contribution of eCBs and CB1R in synapse formation/stabilization as well as the mechanisms by which they exert their effects. Our preliminary findings suggest that we have identified a novel mechanism that plays a important role in regulating synapse number. Studying this will contribute to improve our understanding of fundamental mechanisms that regulate communication between neurons. The combination of pharmacology, transgenic models, molecular biology, immunocytochemistry, electron microscopy, and electrophysiology to study the development and the maturation of synapse will provide an innovative multidisciplinary training environment.**