NeuroEV: Neuronal Extracellular Vesicles and microRNAs in BDNF-dependent hippocampal plasticity

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Extracellular vesicles (EVs) are small lipid-enclosed vesicles secreted by all cells. Small EVs such as exosomes and ectosomes have emerged as novel mediators of inter-cellular communication in several biological systems. Several lines of evidence support a role for EVs as mediators of synaptic plasticity; that is changes in the morphology of synapses following a specific stimulus: 1) EVs were shown to modulate the composition and density of synapses; 2) the trans-synaptic transmission of EVs was demonstrated in different contexts; 3) there are now many examples of functional EV transfer in the brain, for instance between neurons and glia cells or neuroepithelia. Brain-derived neurotrophic factor (BDNF) is a major neuromodulator and mediator of synaptic plasticity. BDNF signaling in the hippocampus is crucial for learning and memory and stress resilience, and decreased levels of BDNF are observed in many disorders characterized by cognitive decline. My preliminary data demonstrate that EVs derived from neurons treated with BDNF can induce the maturation of excitatory synapses in naïve hippocampal neurons. This was not due to the non-specific transfer BDNF, but was rather dependent on the activity of specific EV-microRNAs(miRNAs), small non-coding RNAs that are crucial regulators of neuronal gene expression. The main objectives of this project are: 1) to identify the molecular mechanisms of EV-dependent neuronal synapse morphogenesis downstream EV-miRNAs, 2) to examine the specific contribution of EVs in BDNF-dependent plasticity in vitro using a mouse model that allows transient inhibition of BDNF signaling, and 3) to characterize the spreading of EVs via neuronal synapses in vitro and in hippocampal slices. Given the promising applications of EVs in drug administration and as biomarkers, this project may not only contribute to our understanding of EV neurobiology, it may also uncover potential new approaches for combating disorders characterized by reduced BDNF signaling.