The emerging role of extracellular vesicles-mediated cell-to-cell communication in neural circuits formation

Effective cell-cell communication is fundamental for both formation and function of the central nervous system (CNS), which relies on a precise and dynamic neuronal network. Emerging evidence have pointed out the pivotal role of extracellular vesicles (EVs) in the intercellular interactions occurring within this intricated circuitry. EVs are small particles enclosed in a lipid bilayer released by virtually all cell types, that mediate the transcellular transport of proteins, lipids and nucleic acids between neurons and glial cells. Although the underlying mechanisms of such communication are still rather unknown, it has been shown that under physiological conditions EVs actively contribute to neuronal survival, synaptic formation/plasticity and immune response, thus further raising the interests on EVs and their role on neuronal networks development and function. Given the growing body of research in these last years, the aim of this thesis is to highlight the relevance of intercellular communication mediated by EVs in the context of neuronal connectivity. To achieve this goal, I examined three recent studies concerning the impact exerted by EVs derived from neurons, astrocytes and oligodendrocytes on neuronal circuitry. This analysis takes into account the distinctive cargo composition of these vesicles and the molecular mechanisms underlying the effects induced in the target cells. In the first study, Antoniou et al. (2023) revealed that brain-derived neurotrophic factor (BDNF) induces the sorting of identified microRNA (miRNA) molecules, i.e. miR-132-5p, miR-218-5p, and miR-690, in neuron-derived EVs. These miRNAs-containing EVs enhanced both dendrite complexity and synaptogenesis in recipient hippocampal neurons, and also promoted synchronous neuronal network activity. Subsequently, Patel & Weaver (2021) demonstrated that astrocyte-derived EVs induce both dendritic spine and synapse formation in primary cortical neurons through the delivery of the extracellular matrix protein fibulin-2. The latter acts by activating the transforming growth factor β (TGF-β) signaling in target neurons. Lastly, Chamberlain et al. (2021) analyzed the contribution of oligodendrocyte-derived EVs on supporting axonal energy metabolism, showing that the transfer of the deacetylase sirtuin 2 (SIRT2) to the axon increased mitochondrial ATP production. In addition to providing an overview on neuronal and glial cells functions contributing to the development of connectivity, this dissertation is aimed to underline the key contribution of EVs in this process. As underscored in this text, the diverse roles of EVs in the CNS are strongly dependent on their biogenesis, cargo sorting and release processes. Therefore, despite the promising advances so far, in-depth studies are necessary to shed light on the molecular machinery orchestrating EVs biology in the CNS. Moreover, several promising future EVs applications are also discussed. Their ability to cross biological barriers (e.g.: the blood brain barrier) is of particular interest both for diagnostic and therapeutic purposes. Indeed, EVs potential both as biomarkers for neurodegenerative disorders and for targeted drug-delivery in the treatment of neurological diseases is rapidly emerging. In conclusion, as the prospective applications of EVs have opened a fertile field of research, further work is needed to unveil the molecular mechanisms concerning their role both in physiological and pathological conditions. The study of cell-to-cell communication mediated by EVs represents an innovative and significant approach to deepen our knowledge about CNS functioning and provide novel therapeutic options.