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Blood miR-144-3p: a novel diagnostic and therapeutic tool for depression

Molecular Psychiatry volume 27, pages 4536–4549 (2022)Cite this article

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Abstract

Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression.

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Fig. 1: Schematic outline of experimental design.
Fig. 2: Characterization of circulating miRNAs in ketamine-treated susceptible mice.
Fig. 3: Circulating miR-144-3p levels predict ketamine response in mice.
Fig. 4: Circulating miR-144-3p is associated with MDD severity and ketamine treatment response in MDD patients.
Fig. 5: Systemic knockdown of miR-144-3p reverses behavioral abnormalities exhibited by susceptible mice.
Fig. 6: Transcriptional alterations in blood induced by CSDS are dramatically blunted after miR-144-3p KD.

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Acknowledgements

This work was funded by a grant from Janssen Pharmaceutical Companies, by a grant from the National Institute of Mental Health (R01MH051399 to EJN) and by the Hope for Depression Research Foundation. We wish to thank Drs. Vincent Vialou and Christophe Gerald, previous members of the Mount Sinai research team who worked on the original mouse study.

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  1. Deena M. Walker

    Present address: Department of Behavioral Neuroscience, Oregon Health and Science University School of Medicine, Portland, OR, 97239, USA

Authors and Affiliations

  1. School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, 6229 ER, Maastricht, The Netherlands

    Yentl Y. van der Zee, Lars M. T. Eijssen, Laurence de Nijs & Bart P. F. Rutten

  2. Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Yentl Y. van der Zee, Philipp Mews, Aarthi Ramakrishnan, Kelvin Alvarez, Casey K. Lardner, Hannah M. Cates, Deena M. Walker, Angélica Torres-Berrío, Caleb J. Browne, Ashley Cunningham, Flurin Cathomas, Hope Kronman, Eric M. Parise, Li Shen, James W. Murrough, Eric J. Nestler & Orna Issler

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Contributions

YYZ, OI, and EJN conceived the studies; YYZ performed the mice behavioral and antagomir experiments; YYZ, LMTE, AR, and LS performed the bioinformatic analyses; JWM, KA, and FC performed the human study and provided the human blood and related data; YYZ, OI, PM, CKL, DMW, ATB, AC, EMP, and HK performed mice blood collection; YYZ and OI performed RNA extraction; YYZ performed qPCRs; HMC provided the miRNA Nanostring dataset; OI, EJN, JWM, LMTE, LN, and BPFR contributed to the interpretation of the results; YYZ wrote the manuscript and prepared the figures; OI, EJN, and CJB edited the manuscript; all authors discussed the results and approved the manuscript.

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Correspondence to Eric J. Nestler or Orna Issler.

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van der Zee, Y.Y., Eijssen, L.M.T., Mews, P. et al. Blood miR-144-3p: a novel diagnostic and therapeutic tool for depression. Mol Psychiatry 27, 4536–4549 (2022). https://doi.org/10.1038/s41380-022-01712-6

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