Investigation of Central Nervous System synaptogenesis

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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.