Effects of blood criculating extracellular vesicles on social behaviors in mice: brain gene expression analysis

Extracellular vesicles (EVs) are cell-derived membrane vesicles that circulate throughout the body. Accordingly, circulating EVs and their associated molecules, such as RNAs and proteins, are regarded as promising sources of molecular biomarkers for various disorders. Cell culture-derived EVs have also drawn substantial attention as possible delivery tools for therapeutic molecules. Nevertheless, the biological impact of circulating EVs on in vivo physiology and pathology remains elusive. Here we report that systemic exposure to blood circulating EVs from wild-type (WT) mice attenuates sociability deficits in Rag1-/- mice. Intravenously injected WT mouse blood EVs reach the brain and restore postsynaptic inhibitory signals in the Rag1-/- medial prefrontal cortex (PFC) pyramidal neurons. Mechanistically, WT EV-associated microRNAs, miR-23a-3p and miR-103-3p, reduce PKCε expression, increasing postsynaptic GABAA receptors in the mPFC pyramidal neurons. Our findings reveal a sociability-promoting effect of blood circulating EVs and associated miRNAs with therapeutic potential for sociability deficits.