Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Noncoding RNAs and neurobehavioral mechanisms in psychiatric disease

Molecular Psychiatry volume 20, pages 677–684 (2015)Cite this article

Subjects

Abstract

The human genome project has revolutionized our understanding of the underlying mechanisms in psychiatric disease. It is now abundantly clear that neurobehavioral phenotypes are epigenetically controlled by noncoding RNAs (ncRNAs). The microRNA (miRNA) class of ncRNAs are ubiquitously expressed throughout the brain and govern all major neuronal pathways. The attractive therapeutic potential of miRNAs is underscored by their pleiotropic capacities, putatively targeting multiple pathways within a single neuron. Many psychiatric diseases stem from a multifactorial origin, thus conventional drug targeting of single proteins may not prove most effective. In this exciting post-genome sequencing era, many new epigenetic targets are emerging for therapeutic investigation. Here we review the reported roles of miRNAs, as well as other ncRNA classes, in the pathology of psychiatric disorders; there are both common and unique ncRNA mechanisms that influence the various diagnoses. Collectively, these potent epigenetic regulators may clarify the disrupted signaling networks in psychiatric phenotypes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Kocerha J, Kauppinen S, Wahlestedt C . microRNAs in CNS disorders. Neuromolecular Med 2009; 11: 162–172.

    Article  CAS  PubMed  Google Scholar 

  2. Faghihi MA, Wahlestedt C . Regulatory roles of natural antisense transcripts. Nat Rev Mol Cell Biol 2009; 10: 637–643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sauvageau M, Goff LA, Lodato S, Bonev B, Groff AF, Gerhardinger C et al. Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife 2013; 2: e01749.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Barry G, Mattick JS . The role of regulatory RNA in cognitive evolution. Trends Cogn Sci 2012; 16: 497–503.

    Article  PubMed  Google Scholar 

  5. Bartel DP . MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nam JW, Rissland OS, Koppstein D, Abreu-Goodger C, Jan CH, Agarwal V et al. Global analyses of the effect of different cellular contexts on microRNA targeting. Mol Cell 2014; 53: 1031–1043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gregory RI, Chendrimada TP, Shiekhattar R . MicroRNA biogenesis: isolation and characterization of the microprocessor complex. Methods Mol Biol 2006; 342: 33–47.

    CAS  PubMed  Google Scholar 

  8. Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 2004; 432: 235–240.

    Article  CAS  PubMed  Google Scholar 

  9. Davis TH, Cuellar TL, Koch SM, Barker AJ, Harfe BD, McManus MT et al. Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci 2008; 28: 4322–4330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. De Pietri Tonelli D, Pulvers JN, Haffner C, Murchison EP, Hannon GJ, Huttner WB . miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex. Development 2008; 135: 3911–3921.

    Article  CAS  PubMed  Google Scholar 

  11. Schaefer A, O'Carroll D, Tan CL, Hillman D, Sugimori M, Llinas R et al. Cerebellar neurodegeneration in the absence of microRNAs. J Exp Med 2007; 204: 1553–1558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet 2008; 40: 751–760.

    Article  CAS  PubMed  Google Scholar 

  13. Olde Loohuis NF, Kos A, Martens GJ, Van Bokhoven H, Nadif Kasri N, Aschrafi A . MicroRNA networks direct neuronal development and plasticity. Cell Mol Life Sci 2012; 69: 89–102.

    Article  CAS  PubMed  Google Scholar 

  14. Lugli G, Larson J, Martone ME, Jones Y, Smalheiser NR . Dicer and eIF2c are enriched at postsynaptic densities in adult mouse brain and are modified by neuronal activity in a calpain-dependent manner. J Neurochem 2005; 94: 896–905.

    Article  CAS  PubMed  Google Scholar 

  15. Glanzer J, Miyashiro KY, Sul JY, Barrett L, Belt B, Haydon P et al. RNA splicing capability of live neuronal dendrites. Proc Natl Acad Sci USA 2005; 102: 16859–16864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lugli G, Torvik VI, Larson J, Smalheiser NR . Expression of microRNAs and their precursors in synaptic fractions of adult mouse forebrain. J Neurochem 2008; 106: 650–661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Smalheiser NR . Regulation of mammalian microRNA processing and function by cellular signaling and subcellular localization. Biochim Biophys Acta 2008; 1779: 678–681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Smalheiser NR . Synaptic enrichment of microRNAs in adult mouse forebrain is related to structural features of their precursors. Biol Direct 2008; 3: 44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Siegel G, Saba R, Schratt G . microRNAs in neurons: manifold regulatory roles at the synapse. Curr Opin Genet Dev 2011; 21: 491–497.

    Article  CAS  PubMed  Google Scholar 

  20. Smalheiser NR, Lugli G, Zhang H, Rizavi H, Cook EH, Dwivedi Y . Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects. PLoS One 2014; 9: e86469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bicker S, Lackinger M, Weiss K, Schratt G . MicroRNA-132, -134, and -138: a microRNA troika rules in neuronal dendrites. Cell Mol Life Sci 2014; 71: 3987–4005.

    Article  CAS  PubMed  Google Scholar 

  22. Smalheiser NR, Lugli G . microRNA regulation of synaptic plasticity. Neuromolecular Med 2009; 11: 133–140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun AX, Crabtree GR, Yoo AS . MicroRNAs: regulators of neuronal fate. Curr Opin Cell Biol 2013; 25: 215–221.

    Article  CAS  PubMed  Google Scholar 

  24. Meza-Sosa KF, Pedraza-Alva G, Perez-Martinez L . microRNAs: key triggers of neuronal cell fate. Fron Cell Neurosci 2014; 8: 175.

    Google Scholar 

  25. Pittenger C . Disorders of memory and plasticity in psychiatric disease. Dialogues Clin Neurosci 2013; 15: 455–463.

    PubMed  PubMed Central  Google Scholar 

  26. Zhao C, Sun G, Li S, Lang MF, Yang S, Li W et al. MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling. Proc Natl Acad Sci USA 2010; 107: 1876–1881.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Rybak A, Fuchs H, Smirnova L, Brandt C, Pohl EE, Nitsch R et al. A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nat Cell Biol 2008; 10: 987–993.

    Article  CAS  PubMed  Google Scholar 

  28. Cheng LC, Pastrana E, Tavazoie M, Doetsch F . miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 2009; 12: 399–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu K, Liu Y, Mo W, Qiu R, Wang X, Wu JY et al. MiR-124 regulates early neurogenesis in the optic vesicle and forebrain, targeting NeuroD1. Nucleic Acids Res 2011; 39: 2869–2879.

    Article  CAS  PubMed  Google Scholar 

  30. Papagiannakopoulos T, Kosik KS . MicroRNA-124: micromanager of neurogenesis. Cell stem cell 2009; 4: 375–376.

    Article  CAS  PubMed  Google Scholar 

  31. Zhao C, Sun G, Li S, Shi Y . A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nat Struct Mol Biol 2009; 16: 365–371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gaughwin P, Ciesla M, Yang H, Lim B, Brundin P . Stage-specific modulation of cortical neuronal development by Mmu-miR-134. Cereb Cortex 2011; 21: 1857–1869.

    Article  PubMed  Google Scholar 

  33. Brett JO, Renault VM, Rafalski VA, Webb AE, Brunet A . The microRNA cluster miR-106b~25 regulates adult neural stem/progenitor cell proliferation and neuronal differentiation. Aging 2011; 3: 108–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sun G, Ye P, Murai K, Lang MF, Li S, Zhang H et al. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat Commun 2011; 2: 529.

    Article  CAS  PubMed  Google Scholar 

  35. Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 2008; 6: 14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Smrt RD, Szulwach KE, Pfeiffer RL, Li X, Guo W, Pathania M et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 2010; 28: 1060–1070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Szulwach KE, Li X, Smrt RD, Li Y, Luo Y, Lin L et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol 2010; 189: 127–141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mu Y, Gage FH . Adult hippocampal neurogenesis and its role in Alzheimer's disease. Mol Neurodegener 2011; 6: 85.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Winner B, Rockenstein E, Lie DC, Aigner R, Mante M, Bogdahn U et al. Mutant alpha-synuclein exacerbates age-related decrease of neurogenesis. Neurobiol Aging 2008; 29: 913–925.

    Article  CAS  PubMed  Google Scholar 

  40. Zhao C, Deng W, Gage FH . Mechanisms and functional implications of adult neurogenesis. Cell 2008; 132: 645–660.

    Article  CAS  PubMed  Google Scholar 

  41. Jacobs BL, van Praag H, Gage FH . Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 2000; 5: 262–269.

    Article  CAS  PubMed  Google Scholar 

  42. Rees E, Kirov G, Sanders A, Walters JT, Chambert KD, Shi J et al. Evidence that duplications of 22q11.2 protect against schizophrenia. Mol Psychiatry 2014; 19: 37–40.

    Article  CAS  PubMed  Google Scholar 

  43. Karayiorgou M, Simon TJ, Gogos JA . 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nat Rev Neurosci 2010; 11: 402–416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011; 43: 969–976.

    Article  CAS  Google Scholar 

  45. Ripke S, O'Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 2013; 45: 1150–1159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: 421–427.

    Article  CAS  Google Scholar 

  47. Green MJ, Cairns MJ, Wu J, Dragovic M, Jablensky A, Tooney PA et al. Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia. Mol Psychiatry 2013; 18: 774–780.

    Article  CAS  PubMed  Google Scholar 

  48. Liu B, Zhang X, Hou B, Li J, Qiu C, Qin W et al. The impact of MIR137 on dorsolateral prefrontal-hippocampal functional connectivity in healthy subjects. Neuropsychopharmacology 2014; 39: 2153–2160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lett TA, Chakravarty MM, Felsky D, Brandl EJ, Tiwari AK, Goncalves VF et al. The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia. Mol Psychiatry 2013; 18: 443–450.

    Article  CAS  PubMed  Google Scholar 

  50. Kwon E, Wang W, Tsai LH . Validation of schizophrenia-associated genes CSMD1, C10orf26, CACNA1C and TCF4 as miR-137 targets. Mol Psychiatry 2013; 18: 11–12.

    Article  CAS  PubMed  Google Scholar 

  51. Kim AH, Parker EK, Williamson V, McMichael GO, Fanous AH, Vladimirov VI . Experimental validation of candidate schizophrenia gene ZNF804A as target for hsa-miR-137. Schizophr Res 2012; 141: 60–64.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wright C, Turner JA, Calhoun VD, Perrone-Bizzozero N . Potential impact of miR-137 and its targets in schizophrenia. Front Genet 2013; 4: 58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Collins AL, Kim Y, Bloom RJ, Kelada SN, Sethupathy P, Sullivan PF . Transcriptional targets of the schizophrenia risk gene MIR137. Transl Psychiatry 2014; 4: e404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ . Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry 2010; 15: 1176–1189.

    Article  CAS  PubMed  Google Scholar 

  55. Song HT, Sun XY, Zhang L, Zhao L, Guo ZM, Fan HM et al. A preliminary analysis of association between the down-regulation of microRNA-181b expression and symptomatology improvement in schizophrenia patients before and after antipsychotic treatment. J Psychiatr Res 2014; 54: 134–140.

    Article  PubMed  Google Scholar 

  56. Sun XY, Lu J, Zhang L, Song HT, Zhao L, Fan HM et al. Aberrant microRNA expression in peripheral plasma and mononuclear cells as specific blood-based biomarkers in schizophrenia patients. J Clin Neurosci 2014; 22: 570–574.

    Article  CAS  PubMed  Google Scholar 

  57. Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MG et al. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci USA 2009; 106: 3507–3512.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Remenyi J, van den Bosch MW, Palygin O, Mistry RB, McKenzie C, Macdonald A et al. miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity. PLoS One 2013; 8: e62509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Scott HL, Tamagnini F, Narduzzo KE, Howarth JL, Lee YB, Wong LF et al. MicroRNA-132 regulates recognition memory and synaptic plasticity in the perirhinal cortex. Eur J Neurosci 2012; 36: 2941–2948.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Wibrand K, Pai B, Siripornmongcolchai T, Bittins M, Berentsen B, Ofte ML et al. MicroRNA regulation of the synaptic plasticity-related gene Arc. PLoS One 2012; 7: e41688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wibrand K, Panja D, Tiron A, Ofte ML, Skaftnesmo KO, Lee CS et al. Differential regulation of mature and precursor microRNA expression by NMDA and metabotropic glutamate receptor activation during LTP in the adult dentate gyrus in vivo. Eur J Neurosci 2010; 31: 636–645.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Pathania M, Torres-Reveron J, Yan L, Kimura T, Lin TV, Gordon V et al. miR-132 enhances dendritic morphogenesis, spine density, synaptic integration, and survival of newborn olfactory bulb neurons. PLoS One 2012; 7: e38174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Edbauer D, Neilson JR, Foster KA, Wang CF, Seeburg DP, Batterton MN et al. Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132. Neuron 2010; 65: 373–384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Balu DT, Li Y, Puhl MD, Benneyworth MA, Basu AC, Takagi S et al. Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc Natl Acad Sci USA 2013; 110: E2400–E2409.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Cheng HY, Papp JW, Varlamova O, Dziema H, Russell B, Curfman JP et al. microRNA modulation of circadian-clock period and entrainment. Neuron 2007; 54: 813–829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mohawk JA, Green CB, Takahashi JS . Central and peripheral circadian clocks in mammals. Annu Rev Neurosci 2012; 35: 445–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Asarnow LD, Soehner AM, Harvey AG . Circadian rhythms and psychiatric illness. Curr Opin Psychiatry 2013; 26: 566–571.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Shende VR, Neuendorff N, Earnest DJ . Role of miR-142-3p in the post-transcriptional regulation of the clock gene Bmal1 in the mouse SCN. PLoS One 2013; 8: e65300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lee KH, Kim SH, Lee HR, Kim W, Kim DY, Shin JC et al. MicroRNA-185 oscillation controls circadian amplitude of mouse Cryptochrome 1 via translational regulation. Mol Biol Cell 2013; 24: 2248–2255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Davis CJ, Clinton JM, Krueger JM . MicroRNA 138, let-7b, and 125a inhibitors differentially alter sleep and EEG delta-wave activity in rats. J Appl Physiol (1985) 2012; 113: 1756–1762.

    Article  CAS  Google Scholar 

  71. Zhou W, Li Y, Wang X, Wu L, Wang Y . MiR-206-mediated dynamic mechanism of the mammalian circadian clock. BMC. Syst Biol 2011; 5: 141.

    Google Scholar 

  72. Davis CJ, Clinton JM, Taishi P, Bohnet SG, Honn KA, Krueger JM . MicroRNA 132 alters sleep and varies with time in brain. J Appl Physiol (1985) 2011; 111: 665–672.

    Article  CAS  Google Scholar 

  73. Alvarez-Saavedra M, Antoun G, Yanagiya A, Oliva-Hernandez R, Cornejo-Palma D, Perez-Iratxeta C et al. miRNA-132 orchestrates chromatin remodeling and translational control of the circadian clock. Hum Mol Genet 2011; 20: 731–751.

    Article  CAS  PubMed  Google Scholar 

  74. Saus E, Soria V, Escaramis G, Vivarelli F, Crespo JM, Kagerbauer B et al. Genetic variants and abnormal processing of pre-miR-182, a circadian clock modulator, in major depression patients with late insomnia. Hum Mol Genet 2010; 19: 4017–4025.

    Article  CAS  PubMed  Google Scholar 

  75. Luo W, Sehgal A . Regulation of circadian behavioral output via a MicroRNA-JAK/STAT circuit. Cell 2012; 148: 765–779.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Kadener S, Menet JS, Sugino K, Horwich MD, Weissbein U, Nawathean P et al. A role for microRNAs in the Drosophila circadian clock. Genes Dev 2009; 23: 2179–2191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cardno AG, Owen MJ . Genetic relationships between schizophrenia, bipolar disorder, and schizoaffective disorder. Schizophr Bull 2014; 40: 504–515.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Zhou R, Yuan P, Wang Y, Hunsberger JG, Elkahloun A, Wei Y et al. Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers. Neuropsychopharmacology 2009; 34: 1395–1405.

    Article  CAS  PubMed  Google Scholar 

  79. Rong H, Liu TB, Yang KJ, Yang HC, Wu DH, Liao CP et al. MicroRNA-134 plasma levels before and after treatment for bipolar mania. J Psychiatr Res 2011; 45: 92–95.

    Article  PubMed  Google Scholar 

  80. Croce N, Mathe AA, Gelfo F, Caltagirone C, Bernardini S, Angelucci F . Effects of lithium and valproic acid on BDNF protein and gene expression in an in vitro human neuron-like model of degeneration. J Psychopharmacol 2014; 28: 964–972.

    Article  CAS  PubMed  Google Scholar 

  81. Yasuda S, Liang MH, Marinova Z, Yahyavi A, Chuang DM . The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry 2009; 14: 51–59.

    Article  CAS  PubMed  Google Scholar 

  82. Modarresi F, Faghihi MA, Lopez-Toledano MA, Fatemi RP, Magistri M, Brothers SP et al. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 2012; 30: 453–459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bahi A, Chandrasekar V, Dreyer JL . Selective lentiviral-mediated suppression of microRNA124a in the hippocampus evokes antidepressants-like effects in rats. Psychoneuroendocrinology 2014; 46: 78–87.

    Article  CAS  PubMed  Google Scholar 

  84. Li YJ, Xu M, Gao ZH, Wang YQ, Yue Z, Zhang YX et al. Alterations of serum levels of BDNF-related miRNAs in patients with depression. PLoS One 2013; 8: e63648.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Smalheiser NR, Lugli G, Rizavi HS, Torvik VI, Turecki G, Dwivedi Y . MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects. PloS One 2012; 7: e33201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. He Y, Zhou Y, Xi Q, Cui H, Luo T, Song H et al. Genetic variations in microRNA processing genes are associated with susceptibility in depression. DNA Cell Biol 2012; 31: 1499–1506.

    Article  CAS  PubMed  Google Scholar 

  87. Araragi N, Lesch KP . Serotonin (5-HT) in the regulation of depression-related emotionality: insight from 5-HT transporter and tryptophan hydroxylase-2 knockout mouse models. Curr Drug Targets 2013; 14: 549–570.

    Article  CAS  PubMed  Google Scholar 

  88. Baudry A, Mouillet-Richard S, Schneider B, Launay JM, Kellermann O . miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. Science 2010; 329: 1537–1541.

    Article  CAS  PubMed  Google Scholar 

  89. Launay JM, Mouillet-Richard S, Baudry A, Pietri M, Kellermann O . Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16. Transl Psychiatry 2011; 1: e56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Asan E, Steinke M, Lesch KP . Serotonergic innervation of the amygdala: targets, receptors, and implications for stress and anxiety. Histochem Cell Biol 2013; 139: 785–813.

    Article  CAS  PubMed  Google Scholar 

  91. Issler O, Haramati S, Paul ED, Maeno H, Navon I, Zwang R et al. MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron 2014; 83: 344–360.

    Article  CAS  PubMed  Google Scholar 

  92. Thounaojam MC, Kaushik DK, Basu A . MicroRNAs in the brain: it's regulatory role in neuroinflammation. Mol Neurobiol 2013; 47: 1034–1044.

    Article  CAS  PubMed  Google Scholar 

  93. Rotheneichner P, Lange S, O'Sullivan A, Marschallinger J, Zaunmair P, Geretsegger C et al. Hippocampal neurogenesis and antidepressive therapy: shocking relations. Neural Plast 2014; 2014: 723915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Anacker C . Adult hippocampal neurogenesis in depression: behavioral implications and regulation by the stress system. Curr Top Behav Neurosci 2014; 18: 25–43.

    Article  PubMed  Google Scholar 

  95. Scott KA, Hoban AE, Clarke G, Moloney GM, Dinan TG, Cryan JF . Thinking small: towards microRNA-based therapeutics for anxiety disorders. Expert Opin Investig Drugs 2015; 1–14.

  96. Domschke K . Patho-genetics of posttraumatic stress disorder. Psychiatr Danub 2012; 24: 267–273.

    CAS  PubMed  Google Scholar 

  97. Zhou J, Nagarkatti P, Zhong Y, Ginsberg JP, Singh NP, Zhang J et al. Dysregulation in microRNA expression is associated with alterations in immune functions in combat veterans with post-traumatic stress disorder. PLoS One 2014; 9: e94075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dhabhar FS . Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res 2014; 58: 193–210.

    Article  CAS  PubMed  Google Scholar 

  99. Slavich GM, Irwin MR . From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull 2014; 140: 774–815.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Jones KA, Thomsen C . The role of the innate immune system in psychiatric disorders. Mol Cell Neurosci 2013; 53: 52–62.

    Article  CAS  PubMed  Google Scholar 

  101. Balakathiresan NS, Chandran R, Bhomia M, Jia M, Li H, Maheshwari RK . Serum and amygdala microRNA signatures of posttraumatic stress: fear correlation and biomarker potential. J Psychiatr Res 2014; 57: 65–73.

    Article  PubMed  Google Scholar 

  102. Haramati S, Navon I, Issler O, Ezra-Nevo G, Gil S, Zwang R et al. MicroRNA as repressors of stress-induced anxiety: the case of amygdalar miR-34. J Neurosci 2011; 31: 14191–14203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dias BG, Goodman JV, Ahluwalia R, Easton AE, Andero R, Ressler KJ . Amygdala-dependent fear memory consolidation via miR-34a and Notch signaling. Neuron 2014; 83: 906–918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hanin G, Shenhar-Tsarfaty S, Yayon N, Hoe YY, Bennett ER, Sklan EH et al. Competing targets of microRNA-608 affect anxiety and hypertension. Hum Mol Genet 2014; 23: 4569–4580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Durairaj RV, Koilmani ER . Environmental enrichment modulates glucocorticoid receptor expression and reduces anxiety in Indian field male mouse Mus booduga through up-regulation of microRNA-124a. Gen Comp Endocrinol 2014; 199: 26–32.

    Article  CAS  PubMed  Google Scholar 

  106. Shaltiel G, Hanan M, Wolf Y, Barbash S, Kovalev E, Shoham S et al. Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target. Brain Struct Funct 2013; 218: 59–72.

    Article  CAS  PubMed  Google Scholar 

  107. Jensen KP, Kranzler HR, Stein MB, Gelernter J . The effects of a MAP2K5 microRNA target site SNP on risk for anxiety and depressive disorders. Am J Med Genet B Neuropsychiatr Genet 2014; 165B: 175–183.

    Article  CAS  PubMed  Google Scholar 

  108. Yoon Y, McKenna MC, Rollins DA, Song M, Nuriel T, Gross SS et al. Anxiety-associated alternative polyadenylation of the serotonin transporter mRNA confers translational regulation by hnRNPK. Proc Natl Acad Sci USA 2013; 110: 11624–11629.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Honda M, Kuwano Y, Katsuura-Kamano S, Kamezaki Y, Fujita K, Akaike Y et al. Chronic academic stress increases a group of microRNAs in peripheral blood. PLoS One 2013; 8: e75960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mannironi C, Camon J, De Vito F, Biundo A, De Stefano ME, Persiconi I et al. Acute stress alters amygdala microRNA miR-135a and miR-124 expression: inferences for corticosteroid dependent stress response. PLoS One 2013; 8: e73385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cuellar TL, Davis TH, Nelson PT, Loeb GB, Harfe BD, Ullian E et al. Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration. Proc Natl Acad Sci USA 2008; 105: 5614–5619.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Muinos-Gimeno M, Espinosa-Parrilla Y, Guidi M, Kagerbauer B, Sipila T, Maron E et al. Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways. Biol Psychiatry 2011; 69: 526–533.

    Article  CAS  PubMed  Google Scholar 

  113. Lin Q, Wei W, Coelho CM, Li X, Baker-Andresen D, Dudley K et al. The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory. Nat Neurosci 2011; 14: 1115–1117.

    Article  CAS  PubMed  Google Scholar 

  114. Smalheiser NR, Lugli G, Rizavi HS, Zhang H, Torvik VI, Pandey GN et al. MicroRNA expression in rat brain exposed to repeated inescapable shock: differential alterations in learned helplessness vs. non-learned helplessness. Int J Neuropsychopharmacol 2011; 14: 1315–1325.

    Article  CAS  PubMed  Google Scholar 

  115. Wu J, Xie X . Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression. Genome Biol 2006; 7: R85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Clark BS, Blackshaw S . Long non-coding RNA-dependent transcriptional regulation in neuronal development and disease. Front Genet 2014; 5: 164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ng SY, Lin L, Soh BS, Stanton LW . Long noncoding RNAs in development and disease of the central nervous system. Trends Genet 2013; 29: 461–468.

    Article  CAS  PubMed  Google Scholar 

  118. Bian S, Sun T . Functions of noncoding RNAs in neural development and neurological diseases. Mol Neurobiol 2011; 44: 359–373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Chung DW, Rudnicki DD, Yu L, Margolis RL . A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression. Hum Mol Genet 2011; 20: 3467–3477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK . The DISC locus in psychiatric illness. Mol Psychiatry 2008; 13: 36–64.

    Article  CAS  PubMed  Google Scholar 

  121. Devon RS, Anderson S, Teague PW, Burgess P, Kipari TM, Semple CA et al. Identification of polymorphisms within disrupted in schizophrenia 1 and disrupted in schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. Psychiatr Genet 2001; 11: 71–78.

    Article  CAS  PubMed  Google Scholar 

  122. Millar JK, James R, Brandon NJ, Thomson PA . DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness. Ann Med 2004; 36: 367–378.

    Article  CAS  PubMed  Google Scholar 

  123. Zhong J, Chuang SC, Bianchi R, Zhao W, Lee H, Fenton AA et al. BC1 regulation of metabotropic glutamate receptor-mediated neuronal excitability. J Neurosci 2009; 29: 9977–9986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Maccarrone M, Rossi S, Bari M, De Chiara V, Rapino C, Musella A et al. Abnormal mGlu 5 receptor/endocannabinoid coupling in mice lacking FMRP and BC1 RNA. Neuropsychopharmacology 2010; 35: 1500–1509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Tay Y, Rinn J, Pandolfi PP . The multilayered complexity of ceRNA crosstalk and competition. Nature 2014; 505: 344–352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Faghihi MA, Zhang M, Huang J, Modarresi F, Van der Brug MP, Nalls MA et al. Evidence for natural antisense transcript-mediated inhibition of microRNA function. Genome Biol 2010; 11: R56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS . Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci USA 2008; 105: 716–721.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Lipovich L, Dachet F, Cai J, Bagla S, Balan K, Jia H et al. Activity-dependent human brain coding/noncoding gene regulatory networks. Genetics 2012; 192: 1133–1148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Mercer TR, Qureshi IA, Gokhan S, Dinger ME, Li G, Mattick JS et al. Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Neurosci 2010; 11: 14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Bond AM, Vangompel MJ, Sametsky EA, Clark MF, Savage JC, Disterhoft JF et al. Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry. Nat Neurosci 2009; 12: 1020–1027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK et al. Natural RNA circles function as efficient microRNA sponges. Nature 2013; 495: 384–388.

    Article  CAS  PubMed  Google Scholar 

  132. Taylor MS, Devon RS, Millar JK, Porteous DJ . Evolutionary constraints on the disrupted in schizophrenia locus. Genomics 2003; 81: 67–77.

    Article  CAS  PubMed  Google Scholar 

  133. Johnstone M, Thomson PA, Hall J, McIntosh AM, Lawrie SM, Porteous DJ . DISC1 in schizophrenia: genetic mouse models and human genomic imaging. Schizophr Bull 2011; 37: 14–20.

    Article  PubMed  Google Scholar 

  134. Barry G, Briggs JA, Vanichkina DP, Poth EM, Beveridge NJ, Ratnu VS et al. The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol Psychiatry 2014; 19: 486–494.

    Article  CAS  PubMed  Google Scholar 

  135. Liu Z, Li X, Sun N, Xu Y, Meng Y, Yang C et al. Microarray profiling and co-expression network analysis of circulating lncRNAs and mRNAs associated with major depressive disorder. PLoS One 2014; 9: e93388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Punzi G, Ursini G, Shin JH, Kleinman JE, Hyde TM, Weinberger DR . Increased expression of MARCKS in post-mortem brain of violent suicide completers is related to transcription of a long, noncoding, antisense RNA. Mol Psychiatry 2014; 19: 1057–1059.

    Article  CAS  PubMed  Google Scholar 

  137. Coon SL, Munson PJ, Cherukuri PF, Sugden D, Rath MF, Moller M et al. Circadian changes in long noncoding RNAs in the pineal gland. Proc Natl Acad Sci USA 2012; 109: 13319–13324.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Vollmers C, Schmitz RJ, Nathanson J, Yeo G, Ecker JR, Panda S . Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. Cell Metab 2012; 16: 833–845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Xue Z, Ye Q, Anson SR, Yang J, Xiao G, Kowbel D et al. Transcriptional interference by antisense RNA is required for circadian clock function. Nature 2014; 514: 650–653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Staehler CF, Keller A, Leidinger P, Backes C, Chandran A, Wischhusen J et al. Whole miRNome-wide differential co-expression of microRNAs. Genomics Proteomics Bioinformatics 2012; 10: 285–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Xu J, Li CX, Li YS, Lv JY, Ma Y, Shao TT et al. MiRNA-miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features. Nucleic Acids Res 2011; 39: 825–836.

    Article  CAS  PubMed  Google Scholar 

  142. Choi JK, Yu U, Yoo OJ, Kim S . Differential coexpression analysis using microarray data and its application to human cancer. Bioinformatics 2005; 21: 4348–4355.

    Article  CAS  PubMed  Google Scholar 

  143. Mo WJ, Fu XP, Han XT, Yang GY, Zhang JG, Guo FH et al. A stochastic model for identifying differential gene pair co-expression patterns in prostate cancer progression. BMC Genomics 2009; 10: 340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge that some of the studies mentioned in this review were funded by National Institute of Mental Health (R01MH100616) to YD. KJB is a New York Stem Cell Foundation—Robertson Investigator. The Brennand Laboratory is supported by a Brain and Behavior Young Investigator Grant, National Institute of Health (NIH) grants R01 MH101454 and R01 MH106056 and the New York Stem Cell Foundation. We thank Matthew Daniel for helping to prepare Table 1 on miRNAs in psychiatric disease.

Author information

Author notes

  1. J Kocerha and K J Brennand: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Georgia Southern University, Statesboro, GA, USA

    J Kocerha

  2. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA

    Y Dwivedi

  3. Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    K J Brennand

Authors
  1. J Kocerha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Dwivedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K J Brennand
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Kocerha.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kocerha, J., Dwivedi, Y. & Brennand, K. Noncoding RNAs and neurobehavioral mechanisms in psychiatric disease. Mol Psychiatry 20, 677–684 (2015). https://doi.org/10.1038/mp.2015.30

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.30

This article is cited by

Search

Advanced search

Quick links