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

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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References

  1. Schmidt, H.D., Shelton, R.C. & Duman, R.S. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 36, 2375–2394 (2011).

    Article  CAS  Google Scholar 

  2. Pincus, H.A. et al. Prescribing trends in psychotropic medications: primary care, psychiatry, and other medical specialties. J. Am. Med. Assoc. 279, 526–531 (1998).

    Article  CAS  Google Scholar 

  3. Banthin, J.S. & Miller, G.E. Trends in prescription drug expenditures by Medicaid enrollees. Med. Care 44, I27–I35 (2006).

    Article  Google Scholar 

  4. Chen, Y. et al. Utilization, price, and spending trends for antidepressants in the US Medicaid Program. Res. Social Adm. Pharm. 4, 244–257 (2008).

    Article  Google Scholar 

  5. Qureshi, I.A. & Mehler, M.F. Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nat. Rev. Neurosci. 13, 528–541 (2012).

    Article  CAS  Google Scholar 

  6. Esteller, M. Non-coding RNAs in human disease. Nat. Rev. Genet. 12, 861–874 (2011).

    Article  CAS  Google Scholar 

  7. He, L. & Hannon, G.J. MicroRNAs: small RNAs with a big role in gene regulation. Nat. Rev. Genet. 5, 522–531 (2004).

    Article  CAS  Google Scholar 

  8. Kozomara, A. & Griffiths-Jones, S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39, D152–D157 (2011).

    Article  CAS  Google Scholar 

  9. Kent, W.J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002).

    Article  CAS  Google Scholar 

  10. Meyer, L.R. et al. The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res. 41, D64–D69 (2013).

    Article  CAS  Google Scholar 

  11. Pasquinelli, A.E. et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408, 86–89 (2000).

    Article  CAS  Google Scholar 

  12. Dweep, H., Sticht, C., Pandey, P. & Gretz, N. miRWalk–database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J. Biomed. Inform. 44, 839–847 (2011).

    Article  CAS  Google Scholar 

  13. Betel, D., Wilson, M., Gabow, A., Marks, D.S. & Sander, C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 36, D149–D153 (2008).

    Article  CAS  Google Scholar 

  14. Miranda, K.C. et al. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell 126, 1203–1217 (2006).

    Article  CAS  Google Scholar 

  15. Krüger, J. & Rehmsmeier, M. RNAhybrid: microRNA target prediction easy, fast and flexible. Nucleic Acids Res. 34, W451–W454 (2006).

    Article  Google Scholar 

  16. Lewis, B.P., Burge, C.B. & Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).

    Article  CAS  Google Scholar 

  17. Ernst, C. et al. Confirmation of region-specific patterns of gene expression in the human brain. Neurogenetics 8, 219–224 (2007).

    Article  CAS  Google Scholar 

  18. Ernst, C. et al. Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers. Arch. Gen. Psychiatry 66, 22–32 (2009).

    Article  CAS  Google Scholar 

  19. Sequeira, A. et al. Patterns of gene expression in the limbic system of suicides with and without major depression. Mol. Psychiatry 12, 640–655 (2007).

    Article  CAS  Google Scholar 

  20. Sequeira, A. et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS ONE 4, e6585 (2009).

    Article  Google Scholar 

  21. Pilc, A., Chaki, S., Nowak, G. & Witkin, J.M. Mood disorders: regulation by metabotropic glutamate receptors. Biochem. Pharmacol. 75, 997–1006 (2008).

    Article  CAS  Google Scholar 

  22. Davis, M.J., Haley, T., Duvoisin, R.M. & Raber, J. Measures of anxiety, sensorimotor function, and memory in male and female mGluR4−/− mice. Behav. Brain Res. 229, 21–28 (2012).

    Article  Google Scholar 

  23. Davis, M.J. et al. Role of mGluR4 in acquisition of fear learning and memory. Neuropharmacology 66, 365–372 (2013).

    Article  CAS  Google Scholar 

  24. Célanire, S. & Campo, B. Recent advances in the drug discovery of metabotropic glutamate receptor 4 (mGluR4) activators for the treatment of CNS and non-CNS disorders. Expert Opin. Drug Discov. 7, 261–280 (2012).

    Article  Google Scholar 

  25. Lopez, J.P. et al. Epigenetic regulation of BDNF expression according to antidepressant response. Mol. Psychiatry 18, 398–399 (2013).

    Article  CAS  Google Scholar 

  26. Bocchio-Chiavetto, L. et al. Blood microRNA changes in depressed patients during antidepressant treatment. Eur. Neuropsychopharmacol. 23, 602–611 (2013).

    Article  CAS  Google Scholar 

  27. Soreq, H. & Wolf, Y. NeurimmiRs: microRNAs in the neuroimmune interface. Trends Mol. Med. 17, 548–555 (2011).

    Article  CAS  Google Scholar 

  28. Labuda, M. et al. Linkage disequilibrium analysis in young populations: pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians. Am. J. Hum. Genet. 59, 633–643 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. López-Romero, P. Pre-processing and differential expression analysis of Agilent microRNA arrays using the AgiMicroRna Bioconductor library. BMC Genomics 12, 64 (2011).

    Article  Google Scholar 

  30. Leek, J.T. & Storey, J.D. Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet. 3, 1724–1735 (2007).

    Article  CAS  Google Scholar 

  31. Smyth, G.K. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, Article3 (2004).

    Article  Google Scholar 

  32. Bozdogan, H. Model Selection and akaike's information criterion (AIC): the general theory and its analytical extensions. Psychometrika 52, 345–370 (1987).

    Article  Google Scholar 

  33. Chen, C. et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 33, e179 (2005).

    Article  Google Scholar 

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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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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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