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miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment

Nature Medicine volume 20, pages 764–768 (2014)Cite this article

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Abstract

Major depressive disorder (MDD) is a prevalent mood disorder that is associated with differential prefrontal brain expression patterns1. Treatment of MDD includes a variety of biopsychosocial approaches. In medical practice, antidepressant drugs are the most common treatment for depressive episodes, and they are among the most prescribed medications in North America2,3. Although antidepressants are clearly effective, particularly for moderate to severe depressive episodes, there is variability in how individuals respond to antidepressant treatment. Failure to respond has individual, economic and social consequences for patients and their families4. Several lines of evidence demonstrate that genes are regulated through the activity of microRNAs (miRNAs), which act as fine-tuners and on-off switches of gene expression5,6,7. Here we report on complementary studies using postmortem human brain samples, cellular assays and samples from clinical trials of patients with depression and show that miR-1202, a miRNA specific to primates and enriched in the human brain, is differentially expressed in individuals with depression. Additionally, miR-1202 regulates expression of the gene encoding metabotropic glutamate receptor-4 (GRM4) and predicts antidepressant response at baseline. These results suggest that miR-1202 is associated with the pathophysiology of depression and is a potential target for new antidepressant treatments.

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Figure 1: Expression of miR-1202.
Figure 2: Functional experiments for validation of miR-1202 and GRM4 interaction.
Figure 3: Antidepressant treatment in humans.

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Acknowledgements

We are grateful for the contributions made by the families consenting to donate brain tissue to the Douglas-Bell Canada Brain Bank. We thank A. Ryan and C. Ernst at McGill University for their contributions of chick brain tissue and human NPCs, respectively. This work was supported by operating grants from the Canadian Institutes of Health Research (CIHR) (2008#190734 and 2013#311113), as well as support from the Fonds de recherche du Québec Santé (FRQS) through its network program, Quebec Network on Suicide, Mood Disorders and Related Disorders (RQSHA). J.P.L. received doctoral funding awards from FRQS and CIHR. G.T. is an FRQS chercheur national.

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Authors and Affiliations

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

    Juan Pablo Lopez, Cristiana Cruceanu, Liam Crapper, Benoit Labonte, Gilles Maussion, Jennie P Yang, Volodymyr Yerko, Naguib Mechawar & Gustavo Turecki

  2. Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada

    Raymond Lim & Paul Pavlidis

  3. Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada

    Caroline Fasano, Erika Vigneault & Salah El Mestikawy

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  1. Juan Pablo Lopez
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Contributions

J.P.L. was involved in conducting and coordinating all aspects of the research, including testing feasibility and planning the experiments, processing human and animal tissues, validating results, executing most molecular and cellular experiments, analyzing data, and interpreting and preparing the manuscript. R.L. and P.P. were responsible for bioinformatics and statistical analysis of the miRNA microarray data. C.C. planned and carried out antidepressant treatment of human NPCs and screening for cytotoxic effects. L.C. performed the agonist and antagonist treatment of human NPCs. C.C., L.C. and G.M. were responsible for the maintenance of human NPCs and knockdown cell lines. C.F., E.V. and S.E.M. were responsible for immunocytochemistry, western blotting and imaging analysis. J.P.Y. and V.Y. conducted the experiments involving overexpression and neutralization of miR-1202 effects on HEK 293 cells. B.L. and N.M. participated in the design of the study and interpretation of the data. G.T. conceived, supported and designed this study and was responsible for overseeing the experiments, including all aspects of design, interpretation of data, and preparation of the manuscript and figures. All authors discussed the results presented in the manuscript.

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Correspondence to Gustavo Turecki.

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The authors declare no competing financial interests.

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Supplementary Tables 1–6 and Supplementary Figures 1–12. (PDF 1433 kb)

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Lopez, J., Lim, R., Cruceanu, C. et al. miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment. Nat Med 20, 764–768 (2014). https://doi.org/10.1038/nm.3582

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