Neuronal extracellular vesicles and associated microRNAs induce circuit connectivity downstream BDNF

• Published in: Cell reports (Cambridge) 2023-02, Vol.42 (2), p.112063-112063, Article 112063
• Main Authors: Antoniou, Anna, Auderset, Loic, Kaurani, Lalit, Sebastian, Eva, Zeng, Yuzhou, Allahham, Maria, Cases-Cunillera, Silvia, Schoch, Susanne, Gründemann, Jan, Fischer, Andre, Schneider, Anja
• Format: Article
• Language: English
• Subjects: BDNF; CP: Neuroscience; exosome; extracellular vesicle; microRNA; network connectivity; neural circuit; synapse; synapse clustering
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112063

Extracellular vesicles (EVs) have emerged as mediators of cellular communication, in part via the delivery of associated microRNAs (miRNAs), small non-coding RNAs that regulate gene expression. We show that brain-derived neurotrophic factor (BDNF) mediates the sorting of miR-132-5p, miR-218-5p, and miR-690 in neuron-derived EVs. BDNF-induced EVs in turn increase excitatory synapse formation in recipient hippocampal neurons, which is dependent on the inter-neuronal delivery of these miRNAs. Transcriptomic analysis further indicates the differential expression of developmental and synaptogenesis-related genes by BDNF-induced EVs, many of which are predicted targets of miR-132-5p, miR-218-5p, and miR-690. Furthermore, BDNF-induced EVs up-regulate synaptic vesicle (SV) clustering in a transmissible manner, thereby increasing synaptic transmission and synchronous neuronal activity. As BDNF and EV-miRNAs miR-218 and miR-132 were previously implicated in neuropsychiatric disorders such as anxiety and depression, our results contribute to a better understanding of disorders characterized by aberrant neural circuit connectivity. [Display omitted] •BDNF induces the sorting of specific miRNAs in small extracellular vesicles (EVs)•BDNF-induced EVs increase excitatory synapse clustering via miRNA-218, -132, -690•EVs transmit synaptic phenotypes to secondary neurons downstream BDNF•BDNF-induced EVs promote synchronous neuronal network activity Antoniou et al. describe a mechanism of brain-derived neurotrophic factor (BDNF)-mediated synapse formation via the transfer of neuronal EVs and miRNA cargo. BDNF-stimulated EVs increased synaptic vesicle clustering at pre-synaptic terminals and enhanced synaptic activity and neuronal circuit connectivity, likely by inducing their own propagation within neuronal circuits.