miR-151a-5p in Neuron-Derived Extracellular Vesicles Mediates Antidepressant Response

Major depressive disorder (MDD) lacks accessible molecular markers that reflect brain pathology and monitor treatment response. Using the neuron-specific protein SNAP25, we investigated the cargo of neuron-derived extracellular vesicles (NEVs) isolated from plasma in relation to antidepressant treatment and identified miR-151a-5p as a mediator of treatment response, increasing selectively in responders while remaining low in non-responders. Plasma levels mirrored deficits in human post-mortem brain tissue from the ventral anterior cingulate cortex, a cortical area implicated in MDD. In mice, engineered NEVs enriched with miR-151a-5p delivered cargo selectively to neurons, where miR-151a-5p engaged the RNA-induced silencing complex and regulated genes involved in synaptic networks, including RIMS3 and ELAVL3. Moreover, administration of miR-151a-5p–loaded NEVs in a model of depressive-like behavior produced rapid antidepressant-like effects. Together, these findings identify a vesicle-based mechanism linking peripheral biomarkers to central pathophysiology and demonstrate that miR-151a-5p functions both as a predictor and effector of antidepressant response.