Neuronal extracellular vesicles mediate BDNF-dependent dendritogenesis and synapse maturation via microRNAs

Extracellular vesicles (EVs) are emerging as novel mediators of cellular communication, in part via the delivery of their contents including microRNAs; small non-coding RNAs that regulate gene expression and are crucial for neuronal circuit formation and function. Whether microRNAs are transferred between differentiated neurons is so far unknown. Moreover, the physiological role of EVs in inter-neuronal signaling is largely elusive. We observed that EVs derived from brain-derived neurotrophic factor (BDNF)-treated neurons induced dendrite complexity, synapse maturation and neuronal firing in recipient hippocampal neurons. This was dependent on the activity of three microRNAs, miR-132-5p, miR-218-5p and miR-690, that were specifically up-regulated in BDNF-induced EVs. Transcriptomic analysis further showed the differential expression of genes related to synaptogenesis in BDNF-EV-treated neurons, many of which are conserved targets of these miRNAs. Overall, this work demonstrates a novel mechanism of inter-neuronal communication, which may be highly relevant in neurological disorders characterized by aberrant BDNF signaling. Mouse primary cortical neurons were treated with BDNF (50ng/ml, 20min), prior to isolating small extracellular vesicles (EV) from cell culture media and cell lysates, 16 hours later. Donor cell lysates and corresponding EVs were subjected to small RNA sequencing (Ctrl or BDNF treated). In another set of experiments, EVs derived from Ctrl- or BDNF-treated neurons (Ctrl-EV or BDNF-EV, respectively) were added to primary hippocampal neurons for 24 hours. Hippocampal cell lysates treated with Ctrl, BDNF (50ng/ml, 20min), Ctrl-EV, BDNF-EV were subjected to RNA sequencing