Neuron-Derived Extracellular Vesicles and Antidepressant Response

Extracellular Vesicles

Saeedi, Saumeh, Corina Nagy, Pascal Ibrahim, Susan Rotzinger, Jane Foster, Naguib Mechawar, Sidney Kennedy, and Gustavo Turecki. 2022. “Neuron-Derived Extracellular Vesicles and Antidepressant Response.” Biological Psychiatry 91 (9): S27–28. ‌

Background 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. Our goal was to use peripherally extracted neuron-derived extracellular vesicles (NDEV) to investigate neuronal miRNA changes associated with antidepressant response. Methods 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 NDEV by immunoprecipitation with L1CAM. EV size was measured using tunable resistive pulse sensing, and exosomal miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Results 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). Conclusions Together, this study indicates that changes in peripherally isolated NDEV can act as both a clinically accessible and informative biomarker of ADT response specifically through size and cargo.

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