The role of exosomes in neuronal communication and neurodevelopmental disorders

Exosomes, shortened as EXOs, are small extracellular vesicles surrounded by a lipid bilayer membrane that contain a huge variability of molecules, including proteins, nucleic acids and metabolites. These are carried from the cells in which EXOs are generated, through the inward budding of the plasma membrane, to the recipient ones, where EXOs cargoes are released and responses are elicited. Given that EXOs are secreted by almost all the cells, it is obvious that they play a great variety of roles throughout the whole body; for instance, it was abundantly demonstrated, in the last decades, their involvement in cancer development and in immune responses triggering; however, since few years, their roles in the central nervous system (CNS) emerged, thus creating great interest in researchers. Here it was found out that they mediate intercellular communication, being thus able to regulate many processes, including CNS development, cells differentiation, synaptic plasticity and neuronal excitability. Since EXOs role in the brain is a new field and few is known , the aim of my thesis is to analyse their functions in the CNS, particularly how they are involved in the regulation of neuronal development, in the communication between cells and, finally, in the onset of Rett syndrome, a neurodevelopmental disorder. With this purpose I focused my attention on three works concerning the previously listed aspects. In the first paper, Zhang et al. pointed out that EXOs, carrying an epigenetic regulator called HDAC2 between neurons, modulate dendritic spines formation. Then, an example of cell-to-cell communication was provided by Men and his research group, which demonstrated that miRNAs, carried by neurons derived EXOs, increase glutamate transporters levels in astrocytes, preventing neuronal death and excitotoxicity which are linked to a great number of neurodevelopmental disorders. Lastly, Sharma and colleagues proved that with EXOs treatment it is possible to achieve a significant rescue of neurogenesis, synaptogenesis and connectivity in neurons lacking MeCP2 protein and recapitulating disease phenotypes of RTT. In addition to providing an overview on EXOs roles in the CNS, this thesis is also aimed at underlying EXOs future applications in neurodevelopmental disorders diagnosis and treatment. It was indeed discovered that CNS-derived EXOs can be employed as biomarkers of neurodegenerative diseases since their easy isolation from biofluids, such as the cerebrospinal fluid and the saliva, due to their ability to cross the blood brain barrier. On the other hand, they can be also exploited to treat pathological conditions either using control EXOs or engineering them, becoming thus the more convenient drug-delivery system for CNS, whose cells can be precisely targeted to receive the treatment. Taking these findings together, even though more work is still needed to understand the molecular mechanisms of EXOs, in physiological conditions or in the progression of diseases, it is clear that EXOs represent a noteworthy and innovative tool for neurodevelopmental disorders diagnosis and treatment, whose greatest potential, probably, has yet to be discovered.