Exosomes are a class of extracellular vesicles of endocytic origin, which are released by cells and are accessible in biofluids, such as saliva, urine, and plasma. These vesicles are enriched with small RNA, and they play a role in many physiological processes. In the brain, they are involved in processes including synaptic plasticity, neuronal stress response, cell-to-cell communication and neurogenesis. While exosomes have been implicated previously in cancer and neurodegenerative diseases, research regarding their role in mental disorders remains scarce. Given their functional significance in the brain, investigation in this field is warranted. Additionally, because exosomes can cross the blood–brain barrier, they may serve as accessible biomarkers of neural dysfunction. Studying exosomes may provide information towards diagnosis and therapeutic intervention, and specifically those derived from the brain may provide a mechanistic view of the disease phenotype. This review will discuss the roles of exosomes in the brain, and relate novel findings to current insights into mental disorders.

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Previous work has demonstrated that microRNAs (miRNAs) change as a function of antidepressant treatment (ADT) response. However, it is unclear how representative these peripherally detected miRNA changes are to those occurring in the brain. This study aimed to use peripherally extracted neuron-derived extracellular vesicles (NDEVs) to circumvent these limitations and investigate neuronal miRNA changes associated with antidepressant response. Samples were collected at two time points (baseline and after 8 weeks of follow-up) from depressed patients who responded (N=20) and did not respond (N=20) to escitalopram treatment, as well as controls (N=20). Total extracellular vesicles (EVs) were extracted from plasma, and then further enriched for NDEVs by immunoprecipitation with L1CAM. EV size was measured using tunable resistive pulse sensing, and NDEV miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Characterization of NDEVs revealed they were smaller than other EVs isolated from plasma (p<0.0001), had brain-specific neuronal markers, and contained miRNAs enriched for brain functions (p<0.0001) Furthermore, NDEVs from depressed patients were smaller than controls (p<0.05), and NDEV size increased with ADT response (p<0.01). Finally, changes in NDEV cargo, specifically changes in miR-21-5p, miR-30d-5p and miR-486-5p together (p<0.01), were associated with ADT response. Targets of these three miRNAs were altered in brain tissue from depressed individuals (p<0.05). Together, this study indicates that changes in peripherally isolated NDEVs can act as both a clinically accessible and informative biomarker of ADT response specifically through size and cargo.