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Neuron-derived extracellular vesicles enriched from plasma show altered size and miRNA cargo as a function of antidepressant drug response

Molecular Psychiatry volume 26, pages 7417–7424 (2021)Cite this article

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Abstract

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 (NDEV) 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 NDEV by immunoprecipitation with L1CAM. EVs and NDEVs were characterized, and NDEV miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Characterization of NDEVs revealed that 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 NDEV can act as both a clinically accessible and informative biomarker of ADT response specifically through size and cargo.

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Fig. 1: Discovery cohort and methods.
Fig. 2: NDEV vesicle and cargo characterization.
Fig. 3: NDEV size was altered following ADT and response.
Fig. 4: NDEV miRNA cargo was altered in response to ADT, with some cargo predicting response.

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Acknowledgements

GT holds a Canada Research Chair (Tier 1) and is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374 and EPN161427 (ERA-NET ERA PerMed)), and by the Fonds de recherche du Québec—Santé (FRQS) through the Quebec Network on Suicide, Mood Disorders, and Related Disorders. CAN-BIND is an Integrated Discovery Program carried out in partnership with, and financial support from, the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. Funding support was also provided by a grant from the Ontario Research Fund: Research Excellence (RE-08-027) SD. The Douglas-Bell Canada Brain Bank is supported in part by funding from the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives initiative, and from the Fonds de recherche du Québec—Santé (FRQS) through the Quebec Network on Suicide, Mood Disorders and Related Disorders. SS is funded by the Canadian Institute of Health Research (CIHR).

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Author notes

  1. These authors contributed equally: Saumeh Saeedi, Corina Nagy.

Authors and Affiliations

  1. McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada

    Saumeh Saeedi, Corina Nagy, Pascal Ibrahim, Jean-Francois Théroux, Marina Wakid, Laura M. Fiori, Jennie Yang, Naguib Mechawar & Gustavo Turecki

  2. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Saumeh Saeedi

  3. Department of Psychiatry, McGill University, Montreal, QC, Canada

    Corina Nagy, Naguib Mechawar & Gustavo Turecki

  4. Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada

    Pascal Ibrahim & Marina Wakid

  5. Department of Psychiatry, University Health Network, Krembil Research Institute, University of Toronto, Toronto, ON, Canada

    Susan Rotzinger, Jane A. Foster & Sidney H. Kennedy

  6. St Michael’s Hospital, Li Ka Shing Knowledge Institute, Arthur Sommer Rotenberg Suicide and Depression Studies Program and Centre for Depression and Suicide Studies, Toronto, ON, Canada

    Susan Rotzinger & Sidney H. Kennedy

  7. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada

    Jane A. Foster

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Contributions

Conceptualization: SS, CN, and GT. Methodology: SS, CN, MW, and J-FT. Formal analysis: SS and J-FT. Investigation: SS, CN, MW, PI, LMF, and JY. Writing—original draft: SS, CN, and GT. Writing—review and editing: J-FT, LMF, PI, SR, SHK, JAF, and NM. Resources: SR, SHK, JAF, NM, and GT. Funding acquisition: GT, SR, SHK, JAF, NM.

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Correspondence to Gustavo Turecki.

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Saeedi, S., Nagy, C., Ibrahim, P. et al. Neuron-derived extracellular vesicles enriched from plasma show altered size and miRNA cargo as a function of antidepressant drug response. Mol Psychiatry 26, 7417–7424 (2021). https://doi.org/10.1038/s41380-021-01255-2

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