Journal of the American Academy of Child & Adolescent Psychiatry
Volume 49, Issue 8 , Pages 752-771 , August 2010

Epigenetics and the Biological Basis of Gene × Environment Interactions

  • Rosemary C. Bagot, B.Sc.

      Affiliations

    • Sackler Program for Epigenetics and Psychobiology of McGill University and the Douglas Mental Health University Institute, Montreal, Canada
    • ,
  • Michael J. Meaney, Ph.D.

      Affiliations

    • Sackler Program for Epigenetics and Psychobiology of McGill University and the Douglas Mental Health University Institute, Montreal, Canada
    • Singapore Institute for Clinical Sciences
    • Corresponding Author InformationCorrespondence to Michael Meaney, Ph.D., Sackler Program for Epigenetics and Psychobiology at McGill University, Douglas Mental Health University Institute, 6875 LaSalle Boulevard, Montréal, Québec, Canada H4H 1R3

,Accepted 7 June 2010.

References 

  1. Plomin R, Rutter M. Child development, molecular genetics, and what to do with genes once they are found. Child Dev. 1998;69(4):1223–1242
  2. Kendler KS. Twin studies of psychiatric illness: an update. Arch Gen Psychiatry. 2001;58(11):1005–1014
  3. Ebstein RP. The molecular genetic architecture of human personality: beyond self-report questionnaires. Mol Psychiatry. 2006;11(5):427–445
  4. Rutter M. Gene-environment interdependence. Dev Sci. 2007;10(1):12–18
  5. Meyer-Lindenberg A, Weinberger DR. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci. 2006;7(10):818–827
  6. Harper LV. Epigenetic inheritance and the intergenerational transfer of experience. Psychol Bull. 2005;131(3):340–360
  7. Szyf M, Weaver I, Meaney M. Maternal care, the epigenome and phenotypic differences in behavior. Reprod Toxicol. 2007;24(1):9–19
  8. Zhang TY, Meaney MJ. Epigenetics and the environmental regulation of the genome and its function. Annu Rev Psychol. 2010;61:439–466C431-C433
  9. Waddington CH. The Strategy of the Genes. New York: MacMillan; 1957;
  10. Hake SB, Allis CD. Histone H3 variants and their potential role in indexing mammalian genomes: the “H3 barcode hypothesis.”. 25 Proc Natl Acad Sci U S A. 2006;103(17):6428–6435
  11. Bird A. Perceptions of epigenetics. Nature. 2007;447(7143):396–398
  12. Turner JD, Muller CP. Structure of the glucocorticoid receptor (NR3C1) gene 5′ untranslated region: identification, and tissue distribution of multiple new human exon 1. J Mol Endocrinol. 2005;35(2):283–292
  13. Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 A resolution. 18 Nature. 1997;389(6648):251–260
  14. Turner BM. Chromatin and Gene Regulation: Mechanisms in Epigenetics. Oxford: Blackwell Science; 2001;
  15. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 1997;389(6649):349–352
  16. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074–1080
  17. Bannister AJ, Kouzarides T. The CBP co-activator is a histone acetyltransferase. Nature. 1996;384(6610):641–643
  18. Mellor J. Dynamic nucleosomes and gene transcription. Trends Genet. 2006;22(6):320–329
  19. Akbarian S, Huang HS. Epigenetic regulation in human brain-focus on histone lysine methylation. Biol Psychiatry. 2009;65(3):198–203
  20. Heintzman ND, Stuart RK, Hon G, et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet. 2007;39(3):311–318
  21. Vermeulen M, Mulder KW, Denissov S, et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell. 2007;131(1):58–69
  22. Ooi SK, Qiu C, Bernstein E, et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature. 2007;448(7154):714–717
  23. Berger SL. The complex language of chromatin regulation during transcription. Nature. 2007;447(7143):407–412
  24. Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci. 2007;8(5):355–367
  25. Yang M, Culhane JC, Szewczuk LM, et al. Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. Biochemistry. 2007;46(27):8058–8065
  26. Mitchell JB, Betito K, Rowe W, Boksa P, Meaney MJ. Serotonergic regulation of type II corticosteroid receptor binding in hippocampal cell cultures: evidence for the importance of serotonin-induced changes in cAMP levels. Neuroscience. 1992;48(3):631–639
  27. Mitchell JB, Rowe W, Boksa P, Meaney MJ. Serotonin regulates type II corticosteroid receptor binding in hippocampal cell cultures. J Neurosci. 1990;10(6):1745–1752
  28. Weaver IC, D’Alessio AC, Brown SE, et al. The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes. J Neurosci. 2007;27(7):1756–1768
  29. Weaver IC, Cervoni N, Champagne FA, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7(8):847–854
  30. Hensch TK. Critical period regulation. Annu Rev Neurosci. 2004;27:549–579
  31. Meaney MJ. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci. 2001;24:1161–1192
  32. Champagne FA, Francis DD, Mar A, Meaney MJ. Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol Behav. 2003;79(3):359–371
  33. Champagne FA. Epigenetic mechanisms and the transgenerational effects of maternal care. Front Neuroendocrinol. 2008;29(3):386–397
  34. Schanberg SM, Evoniuk G, Kuhn CM. Tactile and nutritional aspects of maternal care: specific regulators of neuroendocrine function and cellular development. Proc Soc Exp Biol Med. 1984;175(2):135–146
  35. Levine S. The ontogeny of the hypothalamic-pituitary-adrenal axis (The influence of maternal factors). Ann N Y Acad Sci. 1994;746:275–288discussion 289-293
  36. Hofer MA. The psychobiology of early attachment. Clin Neurosci Res. 2005;4:291–300
  37. Liu D, Diorio J, Tannenbaum B, et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science. 1997;277(5332):1659–1662
  38. Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky PM, Meaney MJ. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci U S A. 1998;95(9):5335–5340
  39. Francis D, Diorio J, Liu D, Meaney MJ. Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science. 1999;286(5442):1155–1158
  40. Menard JL, Champagne DL, Meaney MJ. Variations of maternal care differentially influence ‘fear’ reactivity and regional patterns of cFos immunoreactivity in response to the shock-probe burying test. Neuroscience. 2004;129(2):297–308
  41. Bagot RC, van Hasselt FN, Champagne DL, Meaney MJ, Krugers HJ, Joels M. Maternal care determines rapid effects of stress mediators on synaptic plasticity in adult rat hippocampal dentate gyrus. Neurobiol Learn Mem. 2009;92(3):292–300
  42. Toki S, Morinobu S, Imanaka A, Yamamoto S, Yamawaki S, Honma K. Importance of early lighting conditions in maternal care by dam as well as anxiety and memory later in life of offspring. Eur J Neurosci. 2007;25(3):815–829
  43. Caldji C, Diorio J, Meaney MJ. Variations in maternal care alter GABA(A) receptor subunit expression in brain regions associated with fear. Neuropsychopharmacology. 2003;28(11):1950–1959
  44. Plotsky PM, Cunningham ET, Widmaier EP. Catecholaminergic modulation of corticotropin-releasing factor and adrenocorticotropin secretion. Endocr Rev. 1989;10(4):437–458
  45. Koob GF, Heinrichs SC, Pich EM, et al. The role of corticotropin-releasing factor in behavioural responses to stress. Ciba Found Symp. 1993;172:277–289discussion 290-275
  46. Bale TL, Vale WW. CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol. 2004;44:525–557
  47. Jutapakdeegul N, Casalotti SO, Govitrapong P, Kotchabhakdi N. Postnatal touch stimulation acutely alters corticosterone levels and glucocorticoid receptor gene expression in the neonatal rat. Dev Neurosci. 2003;25(1):26–33
  48. Gonzalez A, Lovic V, Ward GR, Wainwright PE, Fleming AS. Intergenerational effects of complete maternal deprivation and replacement stimulation on maternal behavior and emotionality in female rats. Dev Psychobiol. 2001;38(1):11–32
  49. Burton CL, Chatterjee D, Chatterjee-Chakraborty M, et al. Prenatal restraint stress and motherless rearing disrupts expression of plasticity markers and stress-induced corticosterone release in adult female Sprague-Dawley rats. Brain Res. 2007;1158:28–38
  50. Fenoglio KA, Brunson KL, Avishai-Eliner S, Stone BA, Kapadia BJ, Baram TZ. Enduring, handling-evoked enhancement of hippocampal memory function and glucocorticoid receptor expression involves activation of the corticotropin-releasing factor type 1 receptor. Endocrinology. 2005;146(9):4090–4096
  51. Champagne FA, Meaney MJ. Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model. Biol Psychiatry. 2006;59(12):1227–1235
  52. Razin A, Riggs AD. DNA methylation and gene function. Science. 1980;210(4470):604–610
  53. Razin A, Cedar H. Major techniques to study DNA methylation. In:  Jost JP,  Saluz HP editor. DNA Methylation: Molecular Biology and Biological Significance. Basel: Birkhäuser Verlag; 1993;p. 343–359
  54. Holliday R. DNA methylation and epigenetic mechanisms. Cell Biophys. 1989;15(1-2):15–20
  55. Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986;321(6067):209–213
  56. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16(1):6–21
  57. Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006;31(2):89–97
  58. Bird AP, Wolffe AP. Methylation-induced repression—belts, braces, and chromatin. Cell. 1999;99(5):451–454
  59. Bestor TH. Gene silencing (Methylation meets acetylation). Nature. 1998;393(6683):311–312
  60. Razin A. CpG methylation, chromatin structure and gene silencing-a three-way connection. EMBO J. 1998;17(17):4905–4908
  61. Mohandas T, Sparkes RS, Shapiro LJ. Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation. Science. 1981;211(4480):393–396
  62. Riggs AD, Pfeifer GP. X-chromosome inactivation and cell memory. Trends Genet. 1992;8(5):169–174
  63. Hellman A, Chess A. Gene body-specific methylation on the active X chromosome. Science. 2007;315(5815):1141–1143
  64. Reik W, Walter J. Genomic imprinting: parental influence on the genome. Nat Rev Genet. 2001;2(1):21–32
  65. da Rocha ST, Ferguson-Smith AC. Genomic imprinting. Curr Biol. 2004;14(16):R646–R649
  66. Charalambous M, da Rocha ST, Ferguson-Smith AC. Genomic imprinting, growth control and the allocation of nutritional resources: consequences for postnatal life. Curr Opin Endocrinol Diabetes Obes. 2007;14(1):3–12
  67. Weiss A, Cedar H. The role of DNA demethylation during development. Genes Cells. 1997;2(8):481–486
  68. Reik W, Constancia M, Dean W, et al. Igf2 imprinting in development and disease. Int J Dev Biol. 2000;44(1):145–150
  69. Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science. 2003;300(5618):455
  70. Laird PW. Cancer epigenetics. Hum Mol Genet. 2005;14(Spec No 1):R65–R76
  71. Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature. 2007;447(7143):433–440
  72. Meaney MJ, Szyf M. Maternal care as a model for experience-dependent chromatin plasticity?. Trends Neurosci. 2005;28(9):456–463
  73. Fan G, Martinowich K, Chin MH, et al. DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development. 2005;132(15):3345–3356
  74. Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet. 2007;8(4):253–262
  75. Sweatt JD. Experience-dependent epigenetic modifications in the central nervous system. Biol Psychiatry. 2009;65(3):191–197
  76. Cooney CA, Dave AA, Wolff GL. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr. 2002;132(8 Suppl):2393S–2400S
  77. Waterland RA, Lin JR, Smith CA, Jirtle RL. Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet. 2006;15(5):705–716
  78. Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23(15):5293–5300
  79. Whitelaw NC, Whitelaw E. How lifetimes shape epigenotype within and across generations. Hum Mol Genet. 2006;15(Spec No 2):R131–R137
  80. Bruniquel D, Schwartz RH. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol. 2003;4(3):235–240
  81. Murayama A, Sakura K, Nakama M, et al. A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory. EMBO J. 2006;25(5):1081–1092
  82. Martinowich K, Hattori D, Wu H, et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science. 2003;302(5646):890–893
  83. Champagne FA, Weaver IC, Diorio J, Dymov S, Szyf M, Meaney MJ. Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology. 2006;147(6):2909–2915
  84. Lubin FD, Roth TL, Sweatt JD. Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci. 2008;28(42):10576–10586
  85. Gross C, Hen R. The developmental origins of anxiety. Nat Rev Neurosci. 2004;5(7):545–552
  86. Meaney MJ, Diorio J, Francis D, et al. Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: the effects of thyroid hormones and serotonin. J Neurosci. 2000;20(10):3926–3935
  87. Hellstrom IC, Meaney MJ. 2010. Epigenetics and the Environmental Regulation of the Brain’s Genome and its Function. Current Psychiatry Reviews 6: 145-158.
  88. Macleod D, Charlton J, Mullins J, Bird AP. Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island. Genes Dev. 1994;8(19):2282–2292
  89. Brandeis M, Frank D, Keshet I, et al. Sp1 elements protect a CpG island from de novo methylation. Nature. 1994;371(6496):435–438
  90. Kirillov S, Porse BT, Vester B, Woolley P, Garrett RA. Movement of the 3′-end of tRNA through the peptidyl transferase centre and its inhibition by antibiotics. FEBS Lett. 1997;406(3):223–233
  91. Kalkhoven E. CBP and p300: HATs for different occasions. Biochem Pharmacol. 2004;68(6):1145–1155
  92. Szyf M, Weaver IC, Champagne FA, Diorio J, Meaney MJ. Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat. Front Neuroendocrinol. 2005;26(3-4):139–162
  93. Zhang TY, Hellstrom I, Wen XL, Diorio J, Meaney MJ. Naturally occurring variations in maternal behavior modulate hippocampal glutamic acid decarboxylase promoter methylation and glutamic acid decarboxylase expression in rats. Abstract presented at: Developmental Origins and Epigenesis in Human Health and Disease (D1), Singapore, April 2010.
  94. Caldji C, Francis D, Sharma S, Plotsky PM, Meaney MJ. The effects of early rearing environment on the development of GABAA and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat. Neuropsychopharmacology. 2000;22(3):219–229
  95. Fries E, Moragues N, Caldji C, Hellhammer DH, Meaney MJ. Preliminary evidence of altered sensitivity to benzodiazepines as a function of maternal care in the rat. Ann N Y Acad Sci. 2004;1032:320–323
  96. Roth TL, Lubin FD, Funk AJ, Sweatt JD. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry. 2009;65(9):760–769
  97. Murgatroyd C, Patchev AV, Wu Y, et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci. 2009;12(12):1559–1566
  98. McGowan PO, Sasaki A, Huang TCT, Suderman M, Turecki G, Meaney MJ, Szyf M. Epigenetic regulation across an entire chromosomal locus by early life environment. Abstract presented at: Society for Neuroscience, Chicago, October 2009.
  99. Weaver IC, Champagne FA, Brown SE, et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci. 2005;25(47):11045–11054
  100. Weaver IC, Meaney MJ, Szyf M. Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc Natl Acad Sci U S A. 2006;103(9):3480–3485
  101. Dragunow M. A role for immediate-early transcription factors in learning and memory. Behav Genet. 1996;26(3):293–299
  102. O’Donovan KJ, Tourtellotte WG, Millbrandt J, Baraban JM. The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience. Trends Neurosci. 1999;22(4):167–173
  103. Jones MW, Errington ML, French PJ, et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat Neurosci. 2001;4(3):289–296
  104. Knapska E, Kaczmarek L. A gene for neuronal plasticity in the mammalian brain: Zif268/Egr-1/NGFI-A/Krox-24/TIS8/ZENK?. Prog Neurobiol. 2004;74(4):183–211
  105. Li L, Carter J, Gao X, Whitehead J, Tourtellotte WG. The neuroplasticity-associated arc gene is a direct transcriptional target of early growth response (Egr) transcription factors. Mol Cell Biol. 2005;25(23):10286–10300
  106. Liu D, Diorio J, Day JC, Francis DD, Meaney MJ. Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat Neurosci. 2000;3(8):799–806
  107. Bredy TW, Humpartzoomian RA, Cain DP, Meaney MJ. Partial reversal of the effect of maternal care on cognitive function through environmental enrichment. Neuroscience. 2003;118(2):571–576
  108. Champagne DL, Bagot RC, van Hasselt F, et al. Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J Neurosci. 2008;28(23):6037–6045
  109. Malenka RC, Nicoll RA. NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci. 1993;16(12):521–527
  110. Bear MF, Malenka RC. Synaptic plasticity: LTP and LTD. Curr Opin Neurobiol. 1994;4(3):389–399
  111. Morris RG, Frey U. Hippocampal synaptic plasticity: role in spatial learning or the automatic recording of attended experience?. Phi Trans R Soc Lond B Biol Sci. 1997;352(1360):1489–1503
  112. Ali DW, Salter MW. NMDA receptor regulation by Src kinase signalling in excitatory synaptic transmission and plasticity. Curr Opin Neurobiol. 2001;11(3):336–342
  113. Sng J, Meaney MJ. Environmental regulation of the neural epigenome. Epigenomics. 2009;1:131–151
  114. Alberini CM, Ghirardi M, Huang YY, Nguyen PV, Kandel ER. A molecular switch for the consolidation of long-term memory: cAMP-inducible gene expression. Ann N Y Acad Sci. 1995;758:261–286
  115. Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science. 2001;294(5544):1030–1038
  116. Lynch MA. Long-term potentiation and memory. Physiol Rev. 2004;84(1):87–136
  117. Alarcon JM, Malleret G, Touzani K, et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron. 2004;42(6):947–959
  118. Levenson JM, O’Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD. Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem. 2004;279(39):40545–40559
  119. Yeh SH, Lin CH, Gean PW. Acetylation of nuclear factor-kappaB in rat amygdala improves long-term but not short-term retention of fear memory. Mol Pharmacol. 2004;65(5):1286–1292
  120. Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M. Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem. 2007;14(4):268–276
  121. Bourtchouladze R, Lidge R, Catapano R, et al. A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proc Natl Acad Sci U S A. 2003;100(18):10518–10522
  122. Korzus E, Rosenfeld MG, Mayford M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron. 2004;42(6):961–972
  123. Wood MA, Attner MA, Oliveira AM, Brindle PK, Abel T. A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of specific target genes. Learn Mem. 2006;13(5):609–617
  124. Guan Z, Giustetto M, Lomvardas S, et al. Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell. 2002;111(4):483–493
  125. Vecsey CG, Hawk JD, Lattal KM, et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J Neurosci. 2007;27(23):6128–6140
  126. Stefanko DP, Barrett RM, Ly AR, Reolon GK, Wood MA. Modulation of long-term memory for object recognition via HDAC inhibition. Proc Natl Acad Sci U S A. 2009;106(23):9447–9452
  127. Miller CA, Sweatt JD. Covalent modification of DNA regulates memory formation. Neuron. 2007;53(6):857–869
  128. West AE, Chen WG, Dalva MB, et al. Calcium regulation of neuronal gene expression. Proc Natl Acad Sci U S A. 2001;98(20):11024–11031
  129. Timmusk T, Palm K, Metsis M, et al. Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron. 1993;10(3):475–489
  130. Chen WG, Chang Q, Lin Y, et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 2003;302(5646):885–889
  131. Zhou Z, Hong EJ, Cohen S, et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron. 2006;52(2):255–269
  132. Shieh PB, Ghosh A. Molecular mechanisms underlying activity-dependent regulation of BDNF expression. J Neurobiol. 1999;41(1):127–134
  133. Zoghbi HY. Postnatal neurodevelopmental disorders: meeting at the synapse?. Science. 2003;302(5646):826–830
  134. Kishi N, Macklis JD. Dissecting MECP2 function in the central nervous system. J Child Neurol. 2005;20(9):753–759
  135. Moretti P, Levenson JM, Battaglia F, et al. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J Neurosci. 2006;26(1):319–327
  136. Asaka Y, Jugloff DG, Zhang L, Eubanks JH, Fitzsimonds RM. Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis. 2006;21(1):217–227
  137. Nelson ED, Kavalali ET, Monteggia LM. MeCP2-dependent transcriptional repression regulates excitatory neurotransmission. Curr Biol. 2006;16(7):710–716
  138. Pelka GJ, Watson CM, Radziewic T, et al. Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice. Brain. 2006;129(Pt 4):887–898
  139. Lisman J, Schulman H, Cline H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci. 2002;3(3):175–190
  140. Cervoni N, Szyf M. Demethylase activity is directed by histone acetylation. J Biol Chem. 2001;276(44):40778–40787
  141. Wu LP, Wang X, Li L, et al. Histone deacetylase inhibitor depsipeptide activates silenced genes through decreasing both CpG and H3K9 methylation on the promoter. Mol Cell Biol. 2008;28(10):3219–3235
  142. Linnarsson S, Bjorklund A, Ernfors P. Learning deficit in BDNF mutant mice. Eur J Neurosci. 1997;9(12):2581–2587
  143. Hall J, Thomas KL, Everitt BJ. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci. 2000;3(6):533–535
  144. Maren S, Quirk GJ. Neuronal signalling of fear memory. Nat Rev Neurosci. 2004;5(11):844–852
  145. Morris RG, Moser EI, Riedel G, et al. Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. Phil Trans R Soc Lond B Biol Sci. 2003;358(1432):773–786
  146. Roceri M, Hendriks W, Racagni G, Ellenbroek BA, Riva MA. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry. 2002;7(6):609–616
  147. 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(7):708–714
  148. Branchi I, D’Andrea I, Sietzema J, et al. Early social enrichment augments adult hippocampal BDNF levels and survival of BrdU-positive cells while increasing anxiety- and “depression”-like behavior. J Neurosci Res. 2006;83(6):965–973
  149. Lippmann M, Bress A, Nemeroff CB, Plotsky PM, Monteggia LM. Long-term behavioural and molecular alterations associated with maternal separation in rats. Eur J Neurosci. 2007;25(10):3091–3098
  150. Greisen MH, Altar CA, Bolwig TG, Whitehead R, Wortwein G. Increased adult hippocampal brain-derived neurotrophic factor and normal levels of neurogenesis in maternal separation rats. J Neurosci Res. 2005;79(6):772–778
  151. Branchi I, D’Andrea I, Fiore M, Di Fausto V, Aloe L, Alleva E. Early social enrichment shapes social behavior and nerve growth factor and brain-derived neurotrophic factor levels in the adult mouse brain. Biol Psychiatry. 2006;60(7):690–696
  152. Miller FD, Gauthier AS. Timing is everything: making neurons versus glia in the developing cortex. Neuron. 2007;54(3):357–369
  153. Teter B, Rozovsky I, Krohn K, Anderson C, Osterburg H, Finch C. Methylation of the glial fibrillary acidic protein gene shows novel biphasic changes during brain development. Glia. 1996;17(3):195–205
  154. Takizawa T, Nakashima K, Namihira M, et al. DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Dev Cell. 2001;1(6):749–758
  155. Sun YE, Martinowich K, Ge W. Making and repairing the mammalian brain—signaling toward neurogenesis and gliogenesis. Semin Cell Dev Biol. 2003;14(3):161–168
  156. He F, Ge W, Martinowich K, et al. A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci. 2005;8(5):616–625
  157. Kangaspeska S, Stride B, Metivier R, et al. Transient cyclical methylation of promoter DNA. Nature. 2008;452(7183):112–115
  158. Metivier R, Gallais R, Tiffoche C, et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature. 2008;452(7183):45–50
  159. Hall SE, Beverly M, Russ C, Nusbaum C, Sengupta P. A cellular memory of developmental history generates phenotypic diversity in C. elegans. Curr Biol. 2010;26;20(2):149–155
  160. Renthal W, Maze I, Krishnan V, et al. Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron. 2007;56(3):517–529
  161. Renthal W, Nestler EJ. Epigenetic mechanisms in drug addiction. Trends Mol Med. 2008;14(8):341–350
  162. Chahrour M, Jung SY, Shaw C, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008;320(5880):1224–1229
  163. Benes FM, Berretta S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology. 2001;25(1):1–27
  164. Costa E, Davis JM, Dong E, et al. A GABAergic cortical deficit dominates schizophrenia pathophysiology. Crit Rev Neurobiol. 2004;16(1-2):1–23
  165. Akbarian S, Huang HS. Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Res Rev. 2006;52(2):293–304
  166. Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005;6(4):312–324
  167. Straub RE, Lipska BK, Egan MF, et al. Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. Mol Psychiatry. 2007;12(9):854–869
  168. Eastwood SL, Harrison PJ. Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis. Mol Psychiatry. 2003;8(9):769;821-731
  169. Veldic M, Caruncho HJ, Liu WS, et al. DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proc Natl Acad Sci U S A. 2004;101(1):348–353
  170. Abdolmaleky HM, Cheng KH, Russo A, 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(1):60–66
  171. Grayson DR, Jia X, Chen Y, et al. Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci U S A. 2005;102(26):9341–9346
  172. Kundakovic M, Chen Y, Guidotti A, Grayson DR. The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. Mol Pharmacol. 2009;75(2):342–354
  173. McGowan PO, Sasaki A, D’Alessio AC, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009;12(3):342–348
  174. McGirr A, Renaud J, Seguin M, Alda M, Turecki G. Course of major depressive disorder and suicide outcome: a psychological autopsy study. J Clin Psychiatry. 2008;69(6):966–970
  175. Heim C, Newport DJ, Heit S, et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA. 2000;284(5):592–597
  176. Lee R, Geracioti TD, Kasckow JW, Coccaro EF. Childhood trauma and personality disorder: positive correlation with adult CSF corticotropin-releasing factor concentrations. Am J Psychiatry. 2005;162(5):995–997
  177. Schatzberg AF, Rothschild AJ, Langlais PJ, Bird ED, Cole JO. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatr Res. 1985;19(1):57–64
  178. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23(5):477–501
  179. Neigh GN, Nemeroff CB. Reduced glucocorticoid receptors: consequence or cause of depression?. Trends Endocrinol Metab. 2006;17(4):124–125
  180. Ladd-Acosta C, Pevsner J, Sabunciyan S, et al. DNA methylation signatures within the human brain. Am J Hum Genet. 2007;81(6):1304–1315
  181. Sokolowski MB, Wahlsten D. Gene-environment interaction and complex behavior. In:  Moldin SO editors. Methods in Genomic Neuroscience. Boca Raton: CRC Press; 2001;p. 3–27
  182. Weksberg R, Shuman C, Caluseriu O, et al. Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome. Hum Mol Genet. 2002;11(11):1317–1325
  183. Petronis A. Epigenetics and twins: three variations on the theme. Trends Genet. 2006;22(7):347–350
  184. Fraga MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102(30):10604–10609
  185. Mill J, Petronis A. Molecular studies of major depressive disorder: the epigenetic perspective. Mol Psychiatry. 2007;12(9):799–814

 This article is discussed in an editorial by Drs. James J. Hudziak and Stephen V. Faraone on page 729.

 This article can be used to obtain continuing medical education (CME) category 1 credit at jaacap.org in September 2010.

 This is one of several articles published in the August and September issues of the Journal of the American Academy of Child and Adolescent Psychiatry that explores the intersection of genetics and mental health disorders in children and adolescents. The editors invite the reader to investigate the additional articles on this burgeoning area of developmental psychopathology.

 Disclosure: Drs. Bagot and Meaney report no biomedical financial interests or potential conflicts of interest.

PII: S0890-8567(10)00455-7

doi: 10.1016/j.jaac.2010.06.001

Journal of the American Academy of Child & Adolescent Psychiatry
Volume 49, Issue 8 , Pages 752-771 , August 2010

Article Tools

* Image Usage & Resolution