Mechanisms for biogenesis and release of neuronal extracellular vesicles

Neurons release membrane-bound extracellular vesicles (EVs) carrying proteins, nucleic acids, and other cargoes to mediate neuronal development, plasticity, inflammation, regeneration, and degeneration. Functional studies and therapeutic interventions into EV-dependent processes will require a deep understanding of how neuronal EVs are formed and released. However, unraveling EV biogenesis and trafficking mechanisms is challenging, since there are multiple pathways governing generation of different types of EVs, which overlap mechanistically with each other, as well as with intracellular endolysosomal trafficking pathways. Further, neurons present special considerations for EVs due to their extreme morphologies and specialization for membrane traffic. Here, we review recent work elucidating neuronal pathways that regulate EV biogenesis and release, with the goal of identifying directed strategies for experimental and therapeutic targeting of specific types of EVs.