, Volume 10, Issue 4, pp 734–741 | Cite as

Epigenetics and Psychiatry

  • Melissa Mahgoub
  • Lisa M. MonteggiaEmail author


Psychiatric disorders including major depressive disorder, drug addiction, and schizophrenia are debilitating illnesses with a multitude of complex symptoms underlying each of these disorders. In recent years, it has become appreciated that the onset and development of these disorders goes beyond the one gene–one disease approach. Rather, the involvement of many genes is likely linked to these illnesses, and regulating the activation or silencing of gene function may play a crucial role in contributing to their pathophysiology. Epigenetic modifications such as histone acetylation and deacetylation, as well as DNA methylation can induce lasting and stable changes in gene expression, and have therefore been implicated in promoting the adaptive behavioral and neuronal changes that accompany each of these illnesses. In this review we will discuss some of the latest work implicating a potential role for epigenetics in psychiatric disorders, namely, depression, addiction, and schizophrenia as well as a possible role in treatment.


Epigenetics Depression Addiction Schizophrenia Histone 



The authors would like to thank members of the Monteggia laboratory, especially Dr. Megumi Adachi, as well as Dr. Ege Kavalali for helpful discussions and comments on the manuscript. This work was supported by MH081060 (LMM). The authors report no conflicts of interest.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2013_213_MOESM1_ESM.pdf (653 kb)
ESM 1 (PDF 653 kb)


  1. 1.
    Kendler KS. Twin studies of psychiatric illness: an update. Arch Gen Psychiatry 2001;58:1005–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Sapolsky RM. Depression, antidepressants, and the shrinking hippocampus. Proc Natl Acad Sci USA 2001;98:12320–2.PubMedCrossRefGoogle Scholar
  3. 3.
    Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002;34:13–25.PubMedCrossRefGoogle Scholar
  4. 4.
    McEwen BS. Effects of adverse experiences for brain structure and function. Biol Psychiatry 2000;48:721–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Holliday R, Pugh JE. DNA modification mechanisms and gene activity during development. Science 1975;187:226–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003;33 Suppl:245–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell 2007;128:635–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Felsenfeld G, Groudine M. Controlling the double helix. Nature 2003;421:448–53.PubMedCrossRefGoogle Scholar
  9. 9.
    Borrelli E, Nestler EJ, Allis CD, Sassone-Corsi P. Decoding the epigenetic language of neuronal plasticity. Neuron 2008;60:961–74.PubMedCrossRefGoogle Scholar
  10. 10.
    Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986;321:209–13.PubMedCrossRefGoogle Scholar
  11. 11.
    Bird AP, Wolffe AP. Methylation-induced repression--belts, braces, and chromatin. Cell 1999;99:451–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005;74:481–514.PubMedCrossRefGoogle Scholar
  13. 13.
    Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:617–27.PubMedCrossRefGoogle Scholar
  14. 14.
    Fava M, Kendler KS. Major depressive disorder. Neuron 2000;28:335–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Belmaker RH, Agam G. Major depressive disorder. N Engl J Med 2008;358:55–68.PubMedCrossRefGoogle Scholar
  16. 16.
    Castren E, Rantamaki T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Dev Neurobiol 2010;70:289–97.PubMedCrossRefGoogle Scholar
  17. 17.
    Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry 1997;54:597–606.PubMedCrossRefGoogle Scholar
  18. 18.
    Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001;50:260–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997;56:131–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 2002;22:3251–61.PubMedGoogle Scholar
  21. 21.
    Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci USA 2004;101:10827–32.PubMedCrossRefGoogle Scholar
  22. 22.
    Monteggia LM, Luikart B, Barrot M, Theobold D, Malkovska I, Nef S et al. Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol Psychiatry 2007;61:187–97.PubMedCrossRefGoogle Scholar
  23. 23.
    Adachi M, Barrot M, Autry AE, Theobald D, Monteggia LM. Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiatry 2008;63:642–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006;59:1116–27.PubMedCrossRefGoogle Scholar
  25. 25.
    Sapolsky RM. Stress, glucocorticoids, and damage to the nervous system: the current state of confusion. Stress 1996;1:1–19.PubMedCrossRefGoogle Scholar
  26. 26.
    Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995;15:1768–77.PubMedGoogle Scholar
  27. 27.
    Nibuya M, Takahashi M, Russell DS, Duman RS. Repeated stress increases catalytic TrkB mRNA in rat hippocampus. Neurosci Lett 1999;267:81–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Roceri M, Cirulli F, Pessina C, Peretto P, Racagni G, Riva MA. Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions. Biol Psychiatry 2004;55:708–14.PubMedCrossRefGoogle Scholar
  29. 29.
    Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 2006;9:519–25.PubMedCrossRefGoogle Scholar
  30. 30.
    Onishchenko N, Karpova N, Sabri F, Castren E, Ceccatelli S. Long-lasting depression-like behavior and epigenetic changes of BDNF gene expression induced by perinatal exposure to methylmercury. J Neurochem 2008;106:1378–87.PubMedCrossRefGoogle Scholar
  31. 31.
    Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 2006;311:864–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med 2013;19:337–44.PubMedCrossRefGoogle Scholar
  33. 33.
    Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 2012;18:1413–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Nasca C, Xenos D, Barone Y, Caruso A, Scaccianoce S, Matrisciano F et al. L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci USA 2013;110:4804–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Chiechio S, Copani A, Zammataro M, Battaglia G, Gereau RWt, Nicoletti F. Transcriptional regulation of type-2 metabotropic glutamate receptors: an epigenetic path to novel treatments for chronic pain. Trends Pharmacol Sci 2010;31:153–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Overstreet DH, Friedman E, Mathe AA, Yadid G. The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neurosci Biobehav Rev 2005;29:739–59.PubMedCrossRefGoogle Scholar
  37. 37.
    Matrisciano F, Caruso A, Orlando R, Marchiafava M, Bruno V, Battaglia G et al. Defective group-II metaboropic glutamate receptors in the hippocampus of spontaneously depressed rats. Neuropharmacology 2008;55:525–31.PubMedCrossRefGoogle Scholar
  38. 38.
    Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 2010;13:423–30.PubMedCrossRefGoogle Scholar
  39. 39.
    Miller CA, Sweatt JD. Covalent modification of DNA regulates memory formation. Neuron 2007;53:857–69.PubMedCrossRefGoogle Scholar
  40. 40.
    Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P et al. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 2006;281:15763–73.PubMedCrossRefGoogle Scholar
  41. 41.
    LaPlant Q, Vialou V, Covington HE, 3rd, Dumitriu D, Feng J, Warren BL et al. Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci 2010;13:1137–43.PubMedCrossRefGoogle Scholar
  42. 42.
    Nestler EJ. Molecular mechanisms of drug addiction. Neuropharmacology 2004;47 Suppl 1:24–32.PubMedCrossRefGoogle Scholar
  43. 43.
    Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2001;2:119–28.PubMedCrossRefGoogle Scholar
  44. 44.
    Graham DL, Edwards S, Bachtell RK, DiLeone RJ, Rios M, Self DW. Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat Neurosci 2007;10:1029–37.PubMedCrossRefGoogle Scholar
  45. 45.
    Lu L, Dempsey J, Liu SY, Bossert JM, Shaham Y. A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J Neurosci 2004;24:1604–11.PubMedCrossRefGoogle Scholar
  46. 46.
    Grimm JW, Lu L, Hayashi T, Hope BT, Su TP, Shaham Y. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J Neurosci 2003;23:742–7.PubMedGoogle Scholar
  47. 47.
    Im HI, Hollander JA, Bali P, Kenny PJ. MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. Nat Neurosci 2010;13:1120–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DE, Truong HT et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 2005;48:303–14.PubMedCrossRefGoogle Scholar
  49. 49.
    Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 2011;12:623–37.PubMedCrossRefGoogle Scholar
  50. 50.
    Levine AA, Guan Z, Barco A, Xu S, Kandel ER, Schwartz JH. CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum. Proc Natl Acad Sci USA 2005;102:19186–91.PubMedCrossRefGoogle Scholar
  51. 51.
    Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 2009;10:32–42.PubMedCrossRefGoogle Scholar
  52. 52.
    Renthal W, Maze I, Krishnan V, Covington HE, 3rd, Xiao G, Kumar A et al. Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 2007;56:517–29.PubMedCrossRefGoogle Scholar
  53. 53.
    Romieu P, Host L, Gobaille S, Sandner G, Aunis D, Zwiller J. Histone deacetylase inhibitors decrease cocaine but not sucrose self-administration in rats. J Neurosci 2008;28:9342–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Sun J, Wang L, Jiang B, Hui B, Lv Z, Ma L. The effects of sodium butyrate, an inhibitor of histone deacetylase, on the cocaine- and sucrose-maintained self-administration in rats. Neurosci Lett 2008;441:72–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Wang L, Lv Z, Hu Z, Sheng J, Hui B, Sun J et al. Chronic cocaine-induced H3 acetylation and transcriptional activation of CaMKIIalpha in the nucleus accumbens is critical for motivation for drug reinforcement. Neuropsychopharmacology 2010;35:913–28.PubMedCrossRefGoogle Scholar
  56. 56.
    Ferrante RJ, Kubilus JK, Lee J, Ryu H, Beesen A, Zucker B et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J Neurosci 2003;23:9418–27.PubMedGoogle Scholar
  57. 57.
    Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E et al. Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation. Nat Neurosci 2013;16:434–40.PubMedCrossRefGoogle Scholar
  58. 58.
    Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK. The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Arch Gen Psychiatry 1993;50:85–94.PubMedCrossRefGoogle Scholar
  59. 59.
    Carpenter WT, Jr., Buchanan RW. Schizophrenia. N Engl J Med 1994;330:681–90.PubMedCrossRefGoogle Scholar
  60. 60.
    Tamminga CA, Holcomb HH. Phenotype of schizophrenia: a review and formulation. Mol Psychiatry 2005;10:27–39.PubMedCrossRefGoogle Scholar
  61. 61.
    Owen MJ, Williams NM, O'Donovan MC. The molecular genetics of schizophrenia: new findings promise new insights. Mol Psychiatry 2004;9:14–27.PubMedCrossRefGoogle Scholar
  62. 62.
    Costa E, Chen Y, Davis J, Dong E, Noh JS, Tremolizzo L et al. REELIN and schizophrenia: a disease at the interface of the genome and the epigenome. Mol Interv 2002;2:47–57.PubMedCrossRefGoogle Scholar
  63. 63.
    Huang HS, Akbarian S. GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia. PLoS One 2007;2:e809.PubMedCrossRefGoogle Scholar
  64. 64.
    Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 2000;57:1061–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Chen Y, Sharma RP, Costa RH, Costa E, Grayson DR. On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res 2002;30:2930–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Abdolmaleky HM, Cheng KH, Russo A, Smith CL, Faraone SV, Wilcox M et al. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet 2005;134B:60–6.PubMedCrossRefGoogle Scholar
  67. 67.
    Grayson DR, Jia X, Chen Y, Sharma RP, Mitchell CP, Guidotti A et al. Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci USA 2005;102:9341–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Tremolizzo L, Carboni G, Ruzicka WB, Mitchell CP, Sugaya I, Tueting P et al. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc Natl Acad Sci USA 2002;99:17095–100.PubMedCrossRefGoogle Scholar
  69. 69.
    Chen Y, Dong E, Grayson DR. Analysis of the GAD1 promoter: trans-acting factors and DNA methylation converge on the 5' untranslated region. Neuropharmacology 2011;60:1075–87.PubMedCrossRefGoogle Scholar
  70. 70.
    Veldic M, Guidotti A, Maloku E, Davis JM, Costa E. In psychosis, cortical interneurons overexpress DNA-methyltransferase 1. Proc Natl Acad Sci USA 2005;102:2152–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Zhubi A, Veldic M, Puri NV, Kadriu B, Caruncho H, Loza I et al. An upregulation of DNA-methyltransferase 1 and 3a expressed in telencephalic GABAergic neurons of schizophrenia patients is also detected in peripheral blood lymphocytes. Schizophr Res 2009;111:115–22.PubMedCrossRefGoogle Scholar
  72. 72.
    Dong E, Guidotti A, Grayson DR, Costa E. Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters. Proc Natl Acad Sci USA 2007;104:4676–81.PubMedCrossRefGoogle Scholar
  73. 73.
    Kurita M, Holloway T, Garcia-Bea A, Kozlenkov A, Friedman AK, Moreno JL et al. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci 2012;15:1245–54.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2013

Authors and Affiliations

  1. 1.Department of NeuroscienceUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations