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MicroRNAs in Mental Health: From Biological Underpinnings to Potential Therapies

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Abstract

Psychiatric illnesses are disabling disorders with poorly understood underlying pathophysiologies. However, it is becoming increasingly evident that these illnesses result from disruptions across whole cellular networks rather than any particular monoamine system. Recent evidence continues to support the hypothesis that these illnesses arise from impairments in cellular plasticity cascades, which lead to aberrant information processing in the circuits that regulate mood, cognition, and neurovegetative functions (sleep, appetite, energy, etc.). As a result, many have begun to consider future therapies that would be capable of affecting global changes in cellular plasticity to restore appropriate synaptic function and neuronal connectivity. MicroRNAs (miRNAs) are non-coding RNAs that can repress the gene translation of hundreds of their targets and are therefore well-positioned to target a multitude of cellular mechanisms. Here, we review some properties of miRNAs and show they are altered by stress, glucocorticoids, mood stabilizers, and in a particular psychiatric disorder, schizophrenia. While this field is still in its infancy, we consider their potential for regulating behavioral phenotypes and targeting key predicted signaling cascades that are implicated in psychiatric illness. Clearly, considerable research is required to better determine any therapeutic potential of targeting miRNAs; however, these agents may provide the next generation of effective therapies for psychiatric illnesses.

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References

  • Belmaker, R. H., & Agam, G. (2008). Major depressive disorder. New England Journal of Medicine, 358(1), 55–68.

    Article  PubMed  CAS  Google Scholar 

  • Beveridge, N. J., Tooney, P. A., Carroll, A. P., Gardiner, E., Bowden, N., Scott, R. J., et al. (2008). Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. Human Molecular Genetics, 17(8), 1156–1168.

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharyya, S. N., Habermacher, R., Martine, U., Closs, E. I., & Filipowicz, W. (2006). Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell, 125(6), 1111–1124.

    Article  PubMed  CAS  Google Scholar 

  • Bremner, J. D., Elzinga, B., Schmahl, C., & Vermetten, E. (2008). Structural and functional plasticity of the human brain in posttraumatic stress disorder. Progress in Brain Research, 167, 171–186.

    Article  PubMed  CAS  Google Scholar 

  • Cerqueira, J. J., Pego, J. M., Taipa, R., Bessa, J. M., Almeida, O. F., & Sousa, N. (2005). Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors. Journal of Neuroscience, 25(34), 7792–7800.

    Article  PubMed  CAS  Google Scholar 

  • Chaudhuri, K., & Chatterjee, R. (2007). MicroRNA detection and target prediction: Integration of computational and experimental approaches. DNA and Cell Biology, 26(5), 321–337.

    Article  PubMed  CAS  Google Scholar 

  • Chen, G., & Manji, H. K. (2006). The extracellular signal-regulated kinase pathway: An emerging promising target for mood stabilizers. Current Opinion in Psychiatry, 19(3), 313–323.

    Article  PubMed  Google Scholar 

  • Cheng, H. Y., Papp, J. W., Varlamova, O., Dziema, H., Russell, B., Curfman, J. P., et al. (2007). MicroRNA modulation of circadian-clock period and entrainment. Neuron, 54(5), 813–829.

    Article  PubMed  CAS  Google Scholar 

  • Coyle, J. T., & Duman, R. S. (2003). Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron, 38(2), 157–160.

    Article  PubMed  CAS  Google Scholar 

  • Crosby, M. E., Kulshreshtha, R., Ivan, M., & Glazer, P. M. (2009). MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Research, 69(3), 1221–1229.

    Article  PubMed  CAS  Google Scholar 

  • Cryan, J. F., Kelly, P. H., Neijt, H. C., Sansig, G., Flor, P. J., & van Der Putten, H. (2003). Antidepressant and anxiolytic-like effects in mice lacking the group III metabotropic glutamate receptor mGluR7. European Journal of Neuroscience, 17(11), 2409–2417.

    Article  PubMed  Google Scholar 

  • Czeh, B., Perez-Cruz, C., Fuchs, E., & Flugge, G. (2008). Chronic stress-induced cellular changes in the medial prefrontal cortex and their potential clinical implications: Does hemisphere location matter? Behavioural Brain Research, 190(1), 1–13.

    Article  PubMed  Google Scholar 

  • Diorio, D., Viau, V., & Meaney, M. J. (1993). The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. Journal of Neuroscience, 13(9), 3839–3847.

    PubMed  CAS  Google Scholar 

  • Drevets, W. C. (2000). Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Progress in Brain Research, 126, 413–431.

    Article  PubMed  CAS  Google Scholar 

  • Drevets, W. C., Ongur, D., & Price, J. L. (1998). Neuroimaging abnormalities in the subgenual prefrontal cortex: Implications for the pathophysiology of familial mood disorders. Molecular Psychiatry, 3(3), 220–226, 190–221.

    Article  PubMed  CAS  Google Scholar 

  • Drevets, W. C., Price, J. L., Simpson, J. R., Jr., Todd, R. D., Reich, T., Vannier, M., et al. (1997). Subgenual prefrontal cortex abnormalities in mood disorders. Nature, 386(6627), 824–827.

    Article  PubMed  CAS  Google Scholar 

  • Drevets, W. C., Savitz, J., & Trimble, M. (2008). The subgenual anterior cingulate cortex in mood disorders. CNS Spectrums, 13(8), 663–681.

    PubMed  Google Scholar 

  • Duman, R. S. (2004). Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Medicine, 5(1), 11–25.

    Article  PubMed  CAS  Google Scholar 

  • Fish, E. W., Shahrokh, D., Bagot, R., Caldji, C., Bredy, T., Szyf, M., et al. (2004). Epigenetic programming of stress responses through variations in maternal care. Annals of the New York Academy of Sciences, 1036, 167–180.

    Article  PubMed  Google Scholar 

  • Goodwin, F. K., & Jamison, K. R. (2007). Manic-depressive illness: Bipolar disorders and recurrent depression (2nd ed.). Oxford; New York: Oxford University Press.

    Google Scholar 

  • Grippo, A. J., & Johnson, A. K. (2009). Stress, depression and cardiovascular dysregulation: A review of neurobiological mechanisms and the integration of research from preclinical disease models. Stress, 12(1), 1–21.

    Article  PubMed  CAS  Google Scholar 

  • Hansen, T., Olsen, L., Lindow, M., Jakobsen, K. D., Ullum, H., Jonsson, E., et al. (2007). Brain expressed microRNAs implicated in schizophrenia etiology. PLoS ONE, 2(9), e873.

    Article  PubMed  CAS  Google Scholar 

  • Hasler, G., Drevets, W. C., Gould, T. D., Gottesman, I. I., & Manji, H. K. (2006). Toward constructing an behaviroal phenotype strategy for bipolar disorders. Biological Psychiatry, 60(2), 93–105.

    Article  PubMed  Google Scholar 

  • Kato, T. (2008). Molecular neurobiology of bipolar disorder: A disease of ‘mood-stabilizing neurons’? Trends in Neurosciences, 31(10), 495–503.

    Article  PubMed  CAS  Google Scholar 

  • Keck, P. E., Jr., McElroy, S. L., Strakowski, S. M., Stanton, S. P., Kizer, D. L., Balistreri, T. M., et al. (1996). Factors associated with pharmacologic noncompliance in patients with mania. Journal of Clinical Psychiatry, 57(7), 292–297.

    PubMed  CAS  Google Scholar 

  • Kocerha, J., Faghihi, M. A., Lopez-Toledano, M. A., Huang, J., Ramsey, A. J., Caron, M. G., et al. (2009). MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proceedings of the National Academy of Science USA, 106, 3507–3512.

    Article  CAS  Google Scholar 

  • Kupfer, D. J. (2005). The increasing medical burden in bipolar disorder. JAMA, 293(20), 2528–2530.

    Article  PubMed  CAS  Google Scholar 

  • Lang, U. E., Puls, I., Muller, D. J., Strutz-Seebohm, N., & Gallinat, J. (2007). Molecular mechanisms of schizophrenia. Cellular Physiology and Biochemistry, 20(6), 687–702.

    Article  PubMed  CAS  Google Scholar 

  • Leung, A. K., Calabrese, J. M., & Sharp, P. A. (2006). Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules. Proceedings of the National Academy of Science USA, 103(48), 18125–18130.

    Article  CAS  Google Scholar 

  • Leung, A. K., & Sharp, P. A. (2007). microRNAs: A safeguard against turmoil? Cell, 130(4), 581–585.

    Article  PubMed  CAS  Google Scholar 

  • Malleret, G., Haditsch, U., Genoux, D., Jones, M. W., Bliss, T. V., Vanhoose, A. M., et al. (2001). Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell, 104(5), 675–686.

    PubMed  CAS  Google Scholar 

  • Manji, H. K., Gottesman, I. I., & Gould, T. D. (2003). Signal transduction and genes-to-behaviors pathways in psychiatric diseases. Science STKE, 2003(207), pe49.

    Article  Google Scholar 

  • Marsit, C. J., Eddy, K., & Kelsey, K. T. (2006). MicroRNA responses to cellular stress. Cancer Research, 66(22), 10843–10848.

    Article  PubMed  CAS  Google Scholar 

  • McGowan, P. O., Sasaki, A., D’Alessio, A. C., Dymov, S., Labonte, B., Szyf, M., et al. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12(3), 342–348.

    Article  PubMed  CAS  Google Scholar 

  • Miller, M. M., & McEwen, B. S. (2006). Establishing an agenda for translational research on PTSD. Annals of the New York Academy of Sciences, 1071, 294–312.

    Article  PubMed  Google Scholar 

  • Mitsukawa, K., Mombereau, C., Lotscher, E., Uzunov, D. P., van der Putten, H., Flor, P. J., et al. (2006). Metabotropic glutamate receptor subtype 7 ablation causes dysregulation of the HPA axis and increases hippocampal BDNF protein levels: Implications for stress-related psychiatric disorders. Neuropsychopharmacology, 31(6), 1112–1122.

    PubMed  CAS  Google Scholar 

  • Mulkey, R. M., Endo, S., Shenolikar, S., & Malenka, R. C. (1994). Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature, 369(6480), 486–488.

    Article  PubMed  CAS  Google Scholar 

  • Neumeister, A., Wood, S., Bonne, O., Nugent, A. C., Luckenbaugh, D. A., Young, T., et al. (2005). Reduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects. Biological Psychiatry, 57(8), 935–937.

    Article  PubMed  Google Scholar 

  • Perkins, D. O., Jeffries, C. D., Jarskog, L. F., Thomson, J. M., Woods, K., Newman, M. A., et al. (2007). microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biology, 8(2), R27.

    Article  PubMed  CAS  Google Scholar 

  • Pittenger, C., & Duman, R. S. (2008). Stress, depression, and neuroplasticity: A convergence of mechanisms. Neuropsychopharmacology, 33(1), 88–109.

    Article  PubMed  CAS  Google Scholar 

  • Pulkkinen, K., Malm, T., Turunen, M., Koistinaho, J., & Yla-Herttuala, S. (2008). Hypoxia induces microRNA miR-210 in vitro and in vivo ephrin-A3 and neuronal pentraxin 1 are potentially regulated by miR-210. FEBS Letters, 582(16), 2397–2401.

    Article  PubMed  CAS  Google Scholar 

  • Rainer, J., Ploner, C., Jesacher, S., Ploner, A., Eduardoff, M., Mansha, M., et al. (2009). Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia. Leukemia, 23, 746–752.

    Article  PubMed  CAS  Google Scholar 

  • Rajewsky, N. (2006). microRNA target predictions in animals. Nature Genetics, 38(Suppl), S8–S13.

    Article  PubMed  CAS  Google Scholar 

  • Sapolsky, R. M., Romero, L. M., & Munck, A. U. (2000). How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocrine Reviews, 21(1), 55–89.

    Article  PubMed  CAS  Google Scholar 

  • Sethupathy, P., Megraw, M., & Hatzigeorgiou, A. G. (2006). A guide through present computational approaches for the identification of mammalian microRNA targets. Nature Methods, 3(11), 881–886.

    Article  PubMed  CAS  Google Scholar 

  • Shaltiel, G., Chen, G., & Manji, H. K. (2007). Neurotrophic signaling cascades in the pathophysiology and treatment of bipolar disorder. Current Opinion in Pharmacology, 7(1), 22–26.

    Article  PubMed  CAS  Google Scholar 

  • Sklar, P., Smoller, J. W., Fan, J., Ferreira, M. A., Perlis, R. H., Chambert, K., et al. (2008). Whole-genome association study of bipolar disorder. Molecular Psychiatry, 13(6), 558–569.

    Article  PubMed  CAS  Google Scholar 

  • Stark, K. L., Xu, B., Bagchi, A., Lai, W. S., Liu, H., Hsu, R., et al. (2008). Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nature Genetics, 40(6), 751–760.

    Article  PubMed  CAS  Google Scholar 

  • Tabares-Seisdedos, R., & Rubenstein, J. L. (2009). Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: Implications for schizophrenia, autism and cancer. Molecular Psychiatry, 14, 563–589.

    Article  PubMed  CAS  Google Scholar 

  • Uchida, S., Nishida, A., Hara, K., Kamemoto, T., Suetsugi, M., Fujimoto, M., et al. (2008). Characterization of the vulnerability to repeated stress in Fischer 344 rats: Possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor. European Journal of Neuroscience, 27(9), 2250–2261.

    Article  PubMed  Google Scholar 

  • Vreugdenhil, E., Verissimo, C. S., Mariman, R., Kamphorst, J. T., Barbosa, J. S., Zweers, T., et al. (2009). MicroRNAs miR-18 and miR-124a downregulate the glucocorticoid receptor: Implications for glucocorticoid responsiveness in the brain. Endocrinology, 150, 2220–2228.

    Article  PubMed  CAS  Google Scholar 

  • Wang, J. H., & Kelly, P. T. (1997). Postsynaptic calcineurin activity downregulates synaptic transmission by weakening intracellular Ca2+ signaling mechanisms in hippocampal CA1 neurons. Journal of Neuroscience, 17(12), 4600–4611.

    PubMed  CAS  Google Scholar 

  • Weaver, I. C., Cervoni, N., Champagne, F. A., D’Alessio, A. C., Sharma, S., Seckl, J. R., et al. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7(8), 847–854.

    Article  PubMed  CAS  Google Scholar 

  • Wellman, C. L. (2001). Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. Journal of Neurobiology, 49(3), 245–253.

    Article  PubMed  CAS  Google Scholar 

  • Winder, D. G., Mansuy, I. M., Osman, M., Moallem, T. M., & Kandel, E. R. (1998). Genetic and pharmacological evidence for a novel, intermediate phase of long-term potentiation suppressed by calcineurin. Cell, 92(1), 25–37.

    Article  PubMed  CAS  Google Scholar 

  • Yang, M., Lee, J. E., Padgett, R. W., & Edery, I. (2008). Circadian regulation of a limited set of conserved microRNAs in Drosophila. BMC Genomics, 9, 83.

    Article  PubMed  CAS  Google Scholar 

  • Zhou, R., Yuan, P., Wang, Y., Hunsberger, J. G., Elkahloun, A., Wei, Y., et al. (2008). Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers. Neuropsychopharmacology, 34, 1395–1405.

    Article  PubMed  CAS  Google Scholar 

  • Zhu, Y., Kalbfleisch, T., Brennan, M. D., & Li, Y. (2009). A microRNA gene is hosted in an intron of a schizophrenia-susceptibility gene. Schizophrenia Research, 109, 86–89.

    Article  PubMed  Google Scholar 

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Correspondence to Husseini K. Manji.

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Hunsberger, J.G., Austin, D.R., Chen, G. et al. MicroRNAs in Mental Health: From Biological Underpinnings to Potential Therapies. Neuromol Med 11, 173–182 (2009). https://doi.org/10.1007/s12017-009-8070-5

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