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Epigenetic dysregulation in schizophrenia: molecular and clinical aspects of histone deacetylase inhibitors

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Abstract

Notwithstanding the considerable advances in the treatment options for schizophrenia, the cognitive symptoms in particular are not receptive to antipsychotic treatment and considered one of the main predictors for poor social and functional outcome of the disease. Recent findings in preclinical model systems indicate that epigenetic modulation might emerge as a promising target for the treatment of cognitive disorders. The aim of this review is to introduce some of the principles of chromatin biology to the reader and to discuss a possible role in the neurobiology and pathophysiology of schizophrenia. We will discuss potential epigenetic targets for drug therapy, including histone deacetylase inhibitors (HDACi). In a second part, conceptual and practical challenges associated with clinical trials of chromatin-modifying drugs in psychiatric patient populations are discussed, including safety profiles, the potential for adverse effects and general issues revolving around pharmacokinetics and pharmacodynamics. Additional investigations are required in order to fully evaluate the potential of HDACi and similar “epigenetic therapies” as novel treatment options for schizophrenia and other psychotic disease.

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References

  1. Abdolmaleky HM, Cheng KH, Faraone SV, Wilcox M, Glatt SJ, Gao F, Smith CL, Shafa R, Aeali B, Carnevale J, Pan H, Papageorgis P, Ponte JF, Sivaraman V, Tsuang MT, Thiagalingam S (2006) Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet 15:3132–3145

    Article  PubMed  CAS  Google Scholar 

  2. Abujamra AL, Dos Santos MP, Roesler R, Schwartsmann G, Brunetto AL (2010) Histone deacetylase inhibitors: a new perspective for the treatment of leukemia. Leuk Res 34:687–695

    Article  PubMed  CAS  Google Scholar 

  3. Akbarian S, Huang HS (2006) Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Res Rev 52:293–304

    Article  PubMed  CAS  Google Scholar 

  4. Akbarian S, Ruehl MG, Bliven E, Luiz LA, Peranelli AC, Baker SP, Roberts RC, Bunney WE Jr, Conley RC, Jones EG, Tamminga CA, Guo Y (2005) Chromatin alterations associated with down-regulated metabolic gene expression in the prefrontal cortex of subjects with schizophrenia. Arch Gen Psychiatry 62:829–840

    Article  PubMed  CAS  Google Scholar 

  5. Alarcon JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A (2004) Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42:947–959

    Article  PubMed  CAS  Google Scholar 

  6. Allen MH, Hirschfeld RM, Wozniak PJ, Baker JD, Bowden CL (2006) Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania. Am J Psychiatry 163:272–275

    Article  PubMed  Google Scholar 

  7. An der Heiden W, Häfner H (2011) Course and outcome. In: Weinberger D, Harrison P (eds) Schizophrenia, 3rd edn. Wiley-Blackwell, Oxford

    Google Scholar 

  8. Aston C, Jiang L, Sokolov BP (2004) Microarray analysis of postmortem temporal cortex from patients with schizophrenia. J Neurosci Res 77:858–866

    Article  PubMed  CAS  Google Scholar 

  9. Bagnes C, Panchuk PN, Recondo G (2010) Antineoplastic chemotherapy induced QTc prolongation. Curr Drug Saf 5:93–96

    Article  PubMed  CAS  Google Scholar 

  10. Bahari-Javan S, Maddalena A, Kerimoglu C, Wittnam J, Held T, Bahr M, Burkhardt S, Delalle I, Kugler S, Fischer A, Sananbenesi F (2012) HDAC1 regulates fear extinction in mice. J Neurosci 32:5062–5073

    Article  PubMed  CAS  Google Scholar 

  11. Barrett RM, Malvaez M, Kramar E, Matheos DP, Arrizon A, Cabrera SM, Lynch G, Greene RW, Wood MA (2011) Hippocampal focal knockout of CBP affects specific histone modifications, long-term potentiation, and long-term memory. Neuropsychopharmacology 36:1545–1556

    Article  PubMed  CAS  Google Scholar 

  12. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342

    Article  PubMed  CAS  Google Scholar 

  13. Benes FM (2010) Amygdalocortical circuitry in schizophrenia: from circuits to molecules. Neuropsychopharmacology 35:239–257

    Article  PubMed  Google Scholar 

  14. Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M (2007) Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. Proc Natl Acad Sci USA 104:10164–10169

    Article  PubMed  CAS  Google Scholar 

  15. Beneyto M, Kristiansen LV, Oni-Orisan A, McCullumsmith RE, Meador-Woodruff JH (2007) Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 32:1888–1902

    Article  PubMed  CAS  Google Scholar 

  16. Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447:407–412

    Article  PubMed  CAS  Google Scholar 

  17. Bora E, Yucel M, Pantelis C (2009) Cognitive functioning in schizophrenia, schizoaffective disorder and affective psychoses: meta-analytic study. Br J Psychiatry 195:475–482

    Article  PubMed  Google Scholar 

  18. Bousiges O, Vasconcelos AP, Neidl R, Cosquer B, Herbeaux K, Panteleeva I, Loeffler JP, Cassel JC, Boutillier AL (2010) Spatial memory consolidation is associated with induction of several lysine-acetyltransferase (histone acetyltransferase) expression levels and H2B/H4 acetylation-dependent transcriptional events in the rat hippocampus. Neuropsychopharmacology 35:2521–2537

    Article  PubMed  CAS  Google Scholar 

  19. Bruserud O, Stapnes C, Ersvaer E, Gjertsen BT, Ryningen A (2007) Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cell. Curr Pharm Biotechnol 8:388–400

    Article  PubMed  CAS  Google Scholar 

  20. Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W (2010) The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 36:71–93

    Article  PubMed  Google Scholar 

  21. Celegene (2012) Presribing Information ISTODAX (romidepsin) for injection: Update Manufacturing Information 3/2012

  22. Charych EI, Liu F, Moss SJ, Brandon NJ (2009) GABA(A) receptors and their associated proteins: implications in the etiology and treatment of schizophrenia and related disorders. Neuropharmacology 57:481–495

    Article  PubMed  CAS  Google Scholar 

  23. Chiesa A, Chierzi F, De Ronchi D, Serretti A (2012) Quetiapine for bipolar depression: a systematic review and meta-analysis. Int Clin Psychopharmacol 27:76–90

    Article  PubMed  Google Scholar 

  24. Co M (2011) Presribing Information ZOLINZA (vorinostat) capsules: Revised 11/2011

  25. Corporation C (2012) Presribing information ISTODAX (romidepsin) for injection: update manufacturing information 3/2012

  26. Costa E, Chen Y, Dong E, Grayson DR, Kundakovic M, Maloku E, Ruzicka W, Satta R, Veldic M, Zhubi A, Guidotti A (2009) GABAergic promoter hypermethylation as a model to study the neurochemistry of schizophrenia vulnerability. Expert Rev Neurother 9:87–98

    Article  PubMed  CAS  Google Scholar 

  27. Crow TJ (2011) The missing genes: what happened to the heritability of psychiatric disorders? Mol Psychiatry 16:362–364

    Article  PubMed  CAS  Google Scholar 

  28. Daxinger L, Whitelaw E (2012) Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet 13:153–162

    Article  PubMed  CAS  Google Scholar 

  29. Doi M, Hirayama J, Sassone-Corsi P (2006) Circadian regulator CLOCK is a histone acetyltransferase. Cell 125:497–508

    Article  PubMed  CAS  Google Scholar 

  30. Dokmanovic M, Clarke C, Marks PA (2007) Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 5:981–989

    Article  PubMed  CAS  Google Scholar 

  31. Dong E, Nelson M, Grayson DR, Costa E, Guidotti A (2008) Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proc Natl Acad Sci USA 105:13614–13619

    Article  PubMed  CAS  Google Scholar 

  32. Dracheva S, Elhakem SL, McGurk SR, Davis KL, Haroutunian V (2004) GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia. J Neurosci Res 76:581–592

    Article  PubMed  CAS  Google Scholar 

  33. Duncan CE, Webster MJ, Rothmond DA, Bahn S, Elashoff M, Shannon Weickert C (2010) Prefrontal GABA(A) receptor alpha-subunit expression in normal postnatal human development and schizophrenia. J Psychiatr Res 44(10):678–681

    Google Scholar 

  34. Echaniz-Laguna A, Bousiges O, Loeffler JP, Boutillier AL (2008) Histone deacetylase inhibitors: therapeutic agents and research tools for deciphering motor neuron diseases. Curr Med Chem 15:1263–1273

    Article  PubMed  CAS  Google Scholar 

  35. Ederveen TH, Mandemaker IK, Logie C (2011) The human histone H3 complement anno 2011. Biochim Biophys Acta 1809:577–586

    Article  PubMed  CAS  Google Scholar 

  36. Elaut G, Rogiers V, Vanhaecke T (2007) The pharmaceutical potential of histone deacetylase inhibitors. Curr Pharm Des 13:2584–2620

    Article  PubMed  CAS  Google Scholar 

  37. Fischer A, Sananbenesi F, Mungenast A, Tsai LH (2011) Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci 31:605–617

    Article  CAS  Google Scholar 

  38. Gavin DP, Kartan S, Chase K, Grayson DR, Sharma RP (2008) Reduced baseline acetylated histone 3 levels, and a blunted response to HDAC inhibition in lymphocyte cultures from schizophrenia subjects. Schizophr Res 103:330–332

    Article  PubMed  Google Scholar 

  39. Goff DC, Hill M, Barch D (2010) The treatment of cognitive impairment in schizophrenia. Pharmacol Biochem Behav 99:245–253

    Article  PubMed  CAS  Google Scholar 

  40. Gold JM (2004) Cognitive deficits as treatment targets in schizophrenia. Schizophr Res 72:21–28

    Article  PubMed  Google Scholar 

  41. Gottlicher M (2004) Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. Ann Hematol 83(Suppl 1):S91–S92

    PubMed  Google Scholar 

  42. Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20:6969–6978

    Article  PubMed  CAS  Google Scholar 

  43. Govindarajan N, Rao P, Burkhardt S, Sananbenesi F, Schlüter OM, Bradke F, Lu J, Fischer A (2013) Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer’s disease. EMBO Mol Med 5(1):52–63. doi:10.1002/emmm.201201923

    Google Scholar 

  44. Graff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM, Kao PF, Kahn M, Su SC, Samiei A, Joseph N, Haggarty SJ, Delalle I, Tsai LH (2012) An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483:222–226

    Article  PubMed  CAS  Google Scholar 

  45. Grayson DR, Jia X, Chen Y, Sharma RP, Mitchell CP, Guidotti A, Costa E (2005) Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci USA 102:9341–9346

    Article  PubMed  CAS  Google Scholar 

  46. Grayson DR, Kundakovic M, Sharma RP (2010) Is there a future for histone deacetylase inhibitors in the pharmacotherapy of psychiatric disorders? Mol Pharmacol 77:126–135

    Article  PubMed  CAS  Google Scholar 

  47. Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153:321–330

    PubMed  CAS  Google Scholar 

  48. Griswold KS, Pessar LF (2000) Management of bipolar disorder. Am Fam Physician 62:1343–1358

    PubMed  CAS  Google Scholar 

  49. Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60

    Article  PubMed  CAS  Google Scholar 

  50. Guidotti A, Auta J, Chen Y, Davis JM, Dong E, Gavin DP, Grayson DR, Matrisciano F, Pinna G, Satta R, Sharma RP, Tremolizzo L, Tueting P (2011) Epigenetic GABAergic targets in schizophrenia and bipolar disorder. Neuropharmacology 60:1007–1016

    Article  PubMed  CAS  Google Scholar 

  51. Guidotti A, Auta J, Davis JM, Dong E, Grayson DR, Veldic M, Zhang X, Costa E (2005) GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon. Psychopharmacology 180:191–205

    Article  PubMed  CAS  Google Scholar 

  52. Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD, Haroutunian V, Fienberg AA (2001) Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 98:4746–4751

    Article  PubMed  CAS  Google Scholar 

  53. Halene TB, Siegel SJ (2007) PDE inhibitors in psychiatry—future options for dementia, depression and schizophrenia? Drug Discov Today 12:870–878

    Article  PubMed  CAS  Google Scholar 

  54. Hammoud SS, Nix DA, Zhang H, Purwar J, Carrell DT, Cairns BR (2009) Distinctive chromatin in human sperm packages genes for embryo development. Nature 460:473–478

    PubMed  CAS  Google Scholar 

  55. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibault P, Möller HJ (2013) World Federation of Societies of Biological Psychiatry (WFSBP): Guidelines for biological treatment of schizophrenia, Part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatry 14(1):2–44. doi:10.3109/15622975.2012.739708

  56. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Moller HJ (2012) World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 13:318–378

    Article  PubMed  Google Scholar 

  57. Hasan A, Nitsche MA, Rein B, Schneider-Axmann T, Guse B, Gruber O, Falkai P, Wobrock T (2011) Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation. Behav Brain Res 224:15–22

    Article  PubMed  Google Scholar 

  58. Hashimoto T, Bazmi HH, Mirnics K, Wu Q, Sampson AR, Lewis DA (2008) Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. Am J Psychiatry 165:479–489

    Article  PubMed  Google Scholar 

  59. Heinrichs RW, Zakzanis KK (1998) Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12:426–445

    Article  PubMed  CAS  Google Scholar 

  60. Hemby SE, Ginsberg SD, Brunk B, Arnold SE, Trojanowski JQ, Eberwine JH (2002) Gene expression profile for schizophrenia: discrete neuron transcription patterns in the entorhinal cortex. Arch Gen Psychiatry 59:631–640

    Article  PubMed  CAS  Google Scholar 

  61. Hirsch E, Schmitz B, Carreno M (2003) Epilepsy, antiepileptic drugs (AEDs) and cognition. Acta Neurol Scand Suppl 180:23–32

    Article  PubMed  CAS  Google Scholar 

  62. Hoe M, Nakagami E, Green MF, Brekke JS (2012) The causal relationships between neurocognition, social cognition and functional outcome over time in schizophrenia: a latent difference score approach. Psychol Med 42:1–13

    Article  Google Scholar 

  63. Holt DJ, Lebron-Milad K, Milad MR, Rauch SL, Pitman RK, Orr SP, Cassidy BS, Walsh JP, Goff DC (2009) Extinction memory is impaired in schizophrenia. Biol Psychiatry 65:455–463

    Article  PubMed  Google Scholar 

  64. Horan WP, Kern RS, Harvey PO, Green MF (2011) Neurocognition, social cogniton, and functional outcome in schizophrenia. In: Gaebel W (ed) Schizophenia—current science and clinical practice. Wiley, Chichester

    Google Scholar 

  65. Hu E, Dul E, Sung CM, Chen Z, Kirkpatrick R, Zhang GF, Johanson K, Liu R, Lago A, Hofmann G, Macarron R, De Los Frailes M, Perez P, Krawiec J, Winkler J, Jaye M (2003) Identification of novel isoform-selective inhibitors within class I histone deacetylases. J Pharmacol Exp Ther 307:720–728

    Article  PubMed  CAS  Google Scholar 

  66. Huang HS, Akbarian S (2007) GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia. PLoS One 2:e809

    Article  PubMed  CAS  Google Scholar 

  67. Huang HS, Matevossian A, Whittle C, Kim SY, Schumacher A, Baker SP, Akbarian S (2007) Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. J Neurosci 27:11254–11262

    Article  PubMed  CAS  Google Scholar 

  68. Iannitti T, Palmieri B (2011) Clinical and experimental applications of sodium phenylbutyrate. Drugs R D 11:227–249

    Article  PubMed  Google Scholar 

  69. Ibrahim HM, Tamminga CA (2011) Schizophrenia: treatment targets beyond monoamine systems. Annu Rev Pharmacol Toxicol 51:189–209

    Article  PubMed  CAS  Google Scholar 

  70. Iwamoto K, Bundo M, Yamada K, Takao H, Iwayama-Shigeno Y, Yoshikawa T, Kato T (2005) DNA methylation status of SOX10 correlates with its downregulation and oligodendrocyte dysfunction in schizophrenia. J Neurosci 25:5376–5381

    Article  PubMed  CAS  Google Scholar 

  71. Kalin JH, Butler KV, Kozikowski AP (2009) Creating zinc monkey wrenches in the treatment of epigenetic disorders. Curr Opin Chem Biol 13:263–271

    Article  PubMed  CAS  Google Scholar 

  72. Kano S, Colantuoni C, Han F, Zhou Z, Yuan Q, Wilson A, Takayanagi Y, Lee Y, Rapoport J, Eaton W, Cascella N, Ji H, Goldman D, Sawa A (2012) Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia. Mol Psychiatry. doi:10.1038/mp.2012.120

  73. Katsel P, Davis KL, Haroutunian V (2005) Variations in myelin and oligodendrocyte-related gene expression across multiple brain regions in schizophrenia: a gene ontology study. Schizophr Res 79:157–173

    Article  PubMed  Google Scholar 

  74. Kazantsev AG, Thompson LM (2008) Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov 7:854–868

    Article  PubMed  CAS  Google Scholar 

  75. Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N, Qian X, Mills E, Berghs SC, Carey N, Finn PW, Collins LS, Tumber A, Ritchie JW, Jensen PB, Lichenstein HS, Sehested M (2008) Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J 409:581–589

    Article  PubMed  CAS  Google Scholar 

  76. Kinney SM, Chin HG, Vaisvila R, Bitinaite J, Zheng Y, Esteve PO, Feng S, Stroud H, Jacobsen SE, Pradhan S (2011) Tissue-specific distribution and dynamic changes of 5-hydroxymethylcytosine in mammalian genomes. J Biol Chem 286:24685–24693

    Article  PubMed  CAS  Google Scholar 

  77. Korzus E, Rosenfeld MG, Mayford M (2004) CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42:961–972

    Article  PubMed  CAS  Google Scholar 

  78. Kouraklis G, Theocharis S (2006) Histone deacetylase inhibitors: a novel target of anticancer therapy (review). Oncol Rep 15:489–494

    PubMed  CAS  Google Scholar 

  79. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705

    Article  PubMed  CAS  Google Scholar 

  80. Krishnan V, Nestler EJ (2010) Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 167:1305–1320

    Article  PubMed  Google Scholar 

  81. Kundakovic M, Chen Y, Guidotti A, Grayson DR (2009) The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. Mol Pharmacol 75:342–354

    Article  PubMed  CAS  Google Scholar 

  82. Kurita M, Holloway T, Garcia-Bea A, Kozlenkov A, Friedman AK, Moreno JL, Heshmati M, Golden SA, Kennedy PJ, Takahashi N, Dietz DM, Mocci G, Gabilondo AM, Hanks J, Umali A, Callado LF, Gallitano AL, Neve RL, Shen L, Buxbaum JD, Han MH, Nestler EJ, Meana JJ, Russo SJ, Gonzalez-Maeso J (2012) HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci 15:1245–1254

    Article  PubMed  CAS  Google Scholar 

  83. Lattal KM, Barrett RM, Wood MA (2007) Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction. Behav Neurosci 121:1125–1131

    Article  PubMed  CAS  Google Scholar 

  84. Lee H, Dvorak D, Kao HY, Duffy AM, Scharfman HE, Fenton AA (2012) Early cognitive experience prevents adult deficits in a neurodevelopmental schizophrenia model. Neuron 75:714–724

    Article  PubMed  CAS  Google Scholar 

  85. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J (2004) Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 161:1–56

    Article  PubMed  Google Scholar 

  86. Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM (2008) Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci 28:2576–2588

    Article  PubMed  CAS  Google Scholar 

  87. Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324

    Article  PubMed  CAS  Google Scholar 

  88. Li G, Reinberg D (2011) Chromatin higher-order structures and gene regulation. Curr Opin Genet Dev 21:175–186

    Article  PubMed  CAS  Google Scholar 

  89. Li J, Guo Y, Schroeder FA, Youngs RM, Schmidt TW, Ferris C, Konradi C, Akbarian S (2004) Dopamine D2-like antagonists induce chromatin remodeling in striatal neurons through cyclic AMP-protein kinase A and NMDA receptor signaling. J Neurochem 90:1117–1131

    Article  PubMed  CAS  Google Scholar 

  90. Li Q, Barkess G, Qian H (2006) Chromatin looping and the probability of transcription. Trends Genet 22:197–202

    Article  PubMed  CAS  Google Scholar 

  91. Libert S, Pointer K, Bell EL, Das A, Cohen DE, Asara JM, Kapur K, Bergmann S, Preisig M, Otowa T, Kendler KS, Chen X, Hettema JM, van den Oord EJ, Rubio JP, Guarente L (2011) SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive. Cell 147:1459–1472

    Article  PubMed  CAS  Google Scholar 

  92. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223

    Article  PubMed  CAS  Google Scholar 

  93. Lynch DR Jr, Washam JB, Newby LK (2012) QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat: a case report and review of the literature. Cardiol J 19:434–438

    Article  PubMed  Google Scholar 

  94. Martins-de-Souza D, Gattaz WF, Schmitt A, Rewerts C, Marangoni S, Novello JC, Maccarrone G, Turck CW, Dias-Neto E (2009) Alterations in oligodendrocyte proteins, calcium homeostasis and new potential markers in schizophrenia anterior temporal lobe are revealed by shotgun proteome analysis. J Neural Transm 116:275–289

    Article  PubMed  CAS  Google Scholar 

  95. Masetti R, Serravalle S, Biagi C, Pession A (2011) The role of HDACs inhibitors in childhood and adolescence acute leukemias. J Biomed Biotechnol 2011:148046

    Article  PubMed  CAS  Google Scholar 

  96. McQuown SC, Barrett RM, Matheos DP, Post RJ, Rogge GA, Alenghat T, Mullican SE, Jones S, Rusche JR, Lazar MA, Wood MA (2011) HDAC3 is a critical negative regulator of long-term memory formation. J Neurosci 31:764–774

    Article  PubMed  CAS  Google Scholar 

  97. McQuown SC, Wood MA (2011) HDAC3 and the molecular brake pad hypothesis. Neurobiol Learn Mem 96:27–34

    Article  PubMed  CAS  Google Scholar 

  98. Meador-Woodruff JH, Healy DJ (2000) Glutamate receptor expression in schizophrenic brain. Brain Res Brain Res Rev 31:288–294

    Article  PubMed  CAS  Google Scholar 

  99. Merck (2011) Presribing information ZOLINZA (vorinostat) capsules: revised 11/2011

  100. Mesholam-Gately RI, Giuliano AJ, Goff KP, Faraone SV, Seidman LJ (2009) Neurocognition in first-episode schizophrenia: a meta-analytic review. Neuropsychology 23:315–336

    Article  PubMed  Google Scholar 

  101. Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A (2008) Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 82:696–711

    Article  PubMed  CAS  Google Scholar 

  102. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA (2012) Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 17:1206–1227

    Article  PubMed  CAS  Google Scholar 

  103. Mohamed S, Paulsen JS, O’Leary D, Arndt S, Andreasen N (1999) Generalized cognitive deficits in schizophrenia: a study of first-episode patients. Arch Gen Psychiatry 56:749–754

    Article  PubMed  CAS  Google Scholar 

  104. Monsey MS, Ota KT, Akingbade IF, Hong ES, Schafe GE (2011) Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala. PLoS One 6:e19958

    Article  PubMed  CAS  Google Scholar 

  105. Mouri A, Nagai T, Ibi D, Yamada K (2012) Animal models of schizophrenia for molecular and pharmacological intervention and potential candidate molecules. Neurobiol Dis. doi:10.1016/j.nbd.2012.10.025

  106. Narayan PJ, Dragunow M (2010) High content analysis of histone acetylation in human cells and tissues. J Neurosci Methods 193:54–61

    Article  PubMed  CAS  Google Scholar 

  107. Olabi B, Ellison-Wright I, McIntosh AM, Wood SJ, Bullmore E, Lawrie SM (2011) Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiatry 70:88–96

    Article  PubMed  Google Scholar 

  108. Palmer BW, Heaton RK, Paulsen JS, Kuck J, Braff D, Harris MJ, Zisook S, Jeste DV (1997) Is it possible to be schizophrenic yet neuropsychologically normal? Neuropsychology 11:437–446

    Article  PubMed  CAS  Google Scholar 

  109. Palmieri D, Lockman PR, Thomas FC, Hua E, Herring J, Hargrave E, Johnson M, Flores N, Qian Y, Vega-Valle E, Taskar KS, Rudraraju V, Mittapalli RK, Gaasch JA, Bohn KA, Thorsheim HR, Liewehr DJ, Davis S, Reilly JF, Walker R, Bronder JL, Feigenbaum L, Steinberg SM, Camphausen K, Meltzer PS, Richon VM, Smith QR, Steeg PS (2009) Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks. Clin Cancer Res 15:6148–6157

    Article  PubMed  CAS  Google Scholar 

  110. Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, Kang H, Farinelli L, Chen W, Fischer A (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–756

    Article  PubMed  CAS  Google Scholar 

  111. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741

    Article  PubMed  CAS  Google Scholar 

  112. Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661

    Article  PubMed  CAS  Google Scholar 

  113. Regenold WT, Phatak P, Marano CM, Gearhart L, Viens CH, Hisley KC (2007) Myelin staining of deep white matter in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and unipolar major depression. Psychiatry Res 151:179–188

    Article  PubMed  CAS  Google Scholar 

  114. Rehan VK, Liu J, Naeem E, Tian J, Sakurai R, Kwong K, Akbari O, Torday JS (2012) Perinatal nicotine exposure induces asthma in second generation offspring. BMC Med 10:129

    Article  PubMed  CAS  Google Scholar 

  115. Rodriguez-Paredes M, Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nat Med 17:330–339

    Article  PubMed  CAS  Google Scholar 

  116. Sananbenesi F, Fischer A (2009) The epigenetic bottleneck of neurodegenerative and psychiatric diseases. Biol Chem 390:1145–1153

    Article  PubMed  CAS  Google Scholar 

  117. Schmitt A, Hasan A, Gruber O, Falkai P (2011) Schizophrenia as a disorder of disconnectivity. Eur Arch Psychiatry Clin Neurosci 261(Suppl 2):S150–S154

    Article  PubMed  Google Scholar 

  118. Sharma RP, Grayson DR, Gavin DP (2008) Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: analysis of the National Brain Databank microarray collection. Schizophr Res 98:111–117

    Article  PubMed  Google Scholar 

  119. Shulha HP, Cheung I, Whittle C, Wang J, Virgil D, Lin CL, Guo Y, Lessard A, Akbarian S, Weng Z (2012) Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons. Arch Gen Psychiatry 69:314–324

    Article  PubMed  CAS  Google Scholar 

  120. Silverstein SM, Schenkel LS, Valone C, Nuernberger SW (1998) Cognitive deficits and psychiatric rehabilitation outcomes in schizophrenia. Psychiatr Q 69:169–191

    Article  PubMed  CAS  Google Scholar 

  121. Simon M, North JA, Shimko JC, Forties RA, Ferdinand MB, Manohar M, Zhang M, Fishel R, Ottesen JJ, Poirier MG (2011) Histone fold modifications control nucleosome unwrapping and disassembly. Proc Natl Acad Sci USA 108:12711–12716

    Article  PubMed  CAS  Google Scholar 

  122. Simonini MV, Camargo LM, Dong E, Maloku E, Veldic M, Costa E, Guidotti A (2006) The benzamide MS-275 is a potent, long-lasting brain region-selective inhibitor of histone deacetylases. Proc Natl Acad Sci USA 103:1587–1592

    Article  PubMed  CAS  Google Scholar 

  123. Smith DF, MacGregor JT, Hiatt RA, Hooper NK, Wehr CM, Peters B, Goldman LR, Yuan LA, Smith PA, Becker CE (1990) Micronucleated erythrocytes as an index of cytogenetic damage in humans: demographic and dietary factors associated with micronucleated erythrocytes in splenectomized subjects. Cancer Res 50:5049–5054

    PubMed  CAS  Google Scholar 

  124. Snitz BE, Macdonald AW 3rd, Carter CS (2006) Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophr Bull 32:179–194

    Article  PubMed  Google Scholar 

  125. Tamayo JM, Zarate CA Jr, Vieta E, Vazquez G, Tohen M (2010) Level of response and safety of pharmacological monotherapy in the treatment of acute bipolar I disorder phases: a systematic review and meta-analysis. Int J Neuropsychopharmacol 13:813–832

    Article  PubMed  CAS  Google Scholar 

  126. Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, Buchou T, Cheng Z, Rousseaux S, Rajagopal N, Lu Z, Ye Z, Zhu Q, Wysocka J, Ye Y, Khochbin S, Ren B, Zhao Y (2011) Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146:1016–1028

    Article  PubMed  CAS  Google Scholar 

  127. Tandon R, Keshavan MS, Nasrallah HA (2008) Schizophrenia, “just the facts” what we know in 2008. 2. Epidemiology and etiology. Schizophr Res 102:1–18

    Article  PubMed  Google Scholar 

  128. Tang B, Dean B, Thomas EA (2011) Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders. Transl Psychiatry 1:e64

    Article  PubMed  CAS  Google Scholar 

  129. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14:1025–1040

    Article  PubMed  CAS  Google Scholar 

  130. Thornicroft G, Tansella M, Becker T, Knapp M, Leese M, Schene A, Vazquez-Barquero JL (2004) The personal impact of schizophrenia in Europe. Schizophr Res 69:125–132

    Article  PubMed  Google Scholar 

  131. Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB, Starkey M, Webster MJ, Yolken RH, Bahn S (2003) Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362:798–805

    Article  PubMed  CAS  Google Scholar 

  132. Tremolizzo L, Carboni G, Ruzicka WB, Mitchell CP, Sugaya I, Tueting P, Sharma R, Grayson DR, Costa E, Guidotti A (2002) An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc Natl Acad Sci USA 99:17095–17100

    Article  PubMed  CAS  Google Scholar 

  133. Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, Cabrera SM, McDonough CB, Brindle PK, Abel T, Wood MA (2007) Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J Neurosci 27:6128–6140

    Article  PubMed  CAS  Google Scholar 

  134. Wang Z, Yang D, Zhang X, Li T, Li J, Tang Y, Le W (2011) Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLoS One 6:e19229

    Article  PubMed  CAS  Google Scholar 

  135. Woo TU, Kim AM, Viscidi E (2008) Disease-specific alterations in glutamatergic neurotransmission on inhibitory interneurons in the prefrontal cortex in schizophrenia. Brain Res 1218:267–277

    Article  PubMed  CAS  Google Scholar 

  136. Wood MA, Attner MA, Oliveira AM, Brindle PK, Abel T (2006) A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of specific target genes. Learn Mem 13:609–617

    Article  PubMed  CAS  Google Scholar 

  137. Wu Y, Blichowski M, Daskalakis ZJ, Wu Z, Liu CC, Cortez MA, Snead OC 3rd (2011) Evidence that clozapine directly interacts on the GABAB receptor. NeuroReport 22:637–641

    Article  PubMed  CAS  Google Scholar 

  138. Yildirim E, Zhang Z, Uz T, Chen CQ, Manev R, Manev H (2003) Valproate administration to mice increases histone acetylation and 5-lipoxygenase content in the hippocampus. Neurosci Lett 345:141–143

    Article  PubMed  CAS  Google Scholar 

  139. Zhou VW, Goren A, Bernstein BE (2011) Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet 12:7–18

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Work in the authors’ laboratory is supported by grants from the National Institutes of Mental Health (USA).

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The authors reports no conflict of interest as it related to the content of this work.

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Authors and Affiliations

  1. Deparment of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Nussbaumstr. 7, 80336, Munich, Germany

    Alkomiet Hasan

  2. Divsion of Psychiatric Epigenomics, Mount Sinai School of Medicine, New York, NY, USA

    Amanda Mitchell, Tobias Halene & Schahram Akbarian

  3. German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany

    Anja Schneider

  4. Department of Psychiatry and Psychotherapy, University Medical Center, Göttingen, Germany

    Anja Schneider

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  1. Alkomiet Hasan
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  2. Amanda Mitchell
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  3. Anja Schneider
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  4. Tobias Halene
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Correspondence to Alkomiet Hasan.

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Hasan, A., Mitchell, A., Schneider, A. et al. Epigenetic dysregulation in schizophrenia: molecular and clinical aspects of histone deacetylase inhibitors. Eur Arch Psychiatry Clin Neurosci 263, 273–284 (2013). https://doi.org/10.1007/s00406-013-0395-2

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  • DOI: https://doi.org/10.1007/s00406-013-0395-2

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