Circulating extracellular vesicle microRNAs mediate immune modulation of social behavior in mice

Extracellular vesicles (EVs) are cell-derived small membrane vesicles and circulate throughout the body, but the impact of circulating EVs on brain function and behavior remains elusive. Here, we report that wild-type (WT) mouse blood, particularly EVs, increases sociability in socially impaired immunodeficient Rag1 -/- mice, mimicking the effects of WT T cell transfer. These EVs localized to neurons and regulated PKCε expression, GABA A receptor synaptic localization, and inhibitory postsynaptic signaling in prefrontal cortex (PFC) pyramidal neurons. Injection of Rag1 -/- EVs supplemented with miR-23a-3p and miR-103-3p enhanced synaptic function and sociability in Rag1 -/- mice. T cells secreted miR-23a-3p via EVs, and Mir23a -/- T cells failed to increase sociability. Similar beneficial effects of WT blood EVs were observed in additional mouse models with sociability deficits, Cntnap2 -/- and Shank3 -/- mice. These findings uncover a previously unrecognized role of EV miRNAs in mediating immune modulation of synaptic function and social behavior, revealing a novel molecular pathway for immune-neuron communication.