Brain-Derived Neurotrophic Factor Epigenetic Modifications Associated with Schizophrenia-like Phenotype Induced by Prenatal Stress in Mice



      Prenatal stress (PRS) is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that PRS induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ, including the gene for brain-derived neurotrophic factor (BDNF).


      Studying adult offspring of pregnant mice subjected to PRS, we explored the long-term effects of PRS on behavior and on the expression of key chromatin remodeling factors including DNA methyltransferase 1, ten-eleven-translocation hydroxylases, methyl CpG binding protein 2, histone deacetylases, and histone methyltransferases and demethylase in the frontal cortex and hippocampus. We also measured the expression of BDNF.


      Adult PRS offspring demonstrate behavioral abnormalities suggestive of SZ and molecular changes similar to changes seen in postmortem brains of patients with SZ. This includes a significant increase in DNA methyltransferase 1 and ten-eleven-translocation hydroxylase 1 in the frontal cortex and hippocampus but not in cerebellum; no changes in histone deacetylases, histone methyltransferases and demethylases, or methyl CpG binding protein 2, and a significant decrease in Bdnf messenger RNA variants. The decrease of the corresponding Bdnf transcript level was accompanied by an enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at Bdnf gene regulatory regions. In addition, the expression of Bdnf transcripts (IV and IX) correlated positively with social approach in both PRS mice and nonstressed mice.


      Because patients with psychosis and PRS mice show similar epigenetic signature, PRS mice may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with SZ.


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        • Monk C.
        • Spicer J.
        • Champagne F.A.
        Linking prenatal maternal adversity to developmental outcomes in infants: The role of epigenetic pathways.
        Dev Psychopathol. 2012; 24: 1361-1376
        • Markham J.A.
        • Koenig J.I.
        Prenatal stress: Role in psychotic and depressive diseases.
        Psychopharmacology. 2011; 214: 89-106
        • Matrisciano F.
        • Tueting P.
        • Dalal I.
        • Kadriu B.
        • Grayson D.R.
        • Davis J.M.
        • et al.
        Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice.
        Neuropharmacology. 2013; 68: 184-194
        • Gillott A.
        • Standen P.J.
        Levels of anxiety and sources of stress in adults with autism.
        J Intellect Disabil. 2007; 11: 359-370
        • Rice F.
        • Jones I.
        • Thapar A.
        The impact of gestational stress and prenatal growth on emotional problems in offspring: A review.
        Acta Psychiatr Scand. 2007; 115: 171-183
        • Walker F.R.
        • Knott B.
        • Hodgson D.M.
        Neonatal endotoxin exposure modifies the acoustic startle response and circulating levels of corticosterone in the adult rat but only following acute stress.
        J Psychiatr Res. 2008; 42: 1094-1103
        • Charil A.
        • Laplante D.P.
        • Vaillancourt C.
        • King S.
        Prenatal stress and brain development.
        Brain Res Rev. 2010; 65: 56-79
        • Matrisciano F.
        • Tueting P.
        • Maccari S.
        • Nicoletti F.
        • Guidotti A.
        Pharmacological activation of group-II metabotropic glutamate receptors corrects a schizophrenia-like phenotype induced by prenatal stress in mice.
        Neuropsychopharmacology. 2012; 37: 929-938
        • McGowan P.O.
        • Szyf M.
        The epigenetics of social adversity in early life: Implications for mental health outcomes.
        Neurobiol Dis. 2010; 39: 66-72
        • Zhang T.Y.
        • Labonté B.
        • Wen X.L.
        • Turecki G.
        • Meaney M.J.
        Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans.
        Neuropsychopharmacology. 2013; 38: 111-123
        • Boersma G.J.
        • Lee R.S.
        • Cordner Z.A.
        • Ewald E.R.
        • Purcell R.H.
        • Moghadam A.A.
        • et al.
        Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats.
        Epigenetics. 2014; 9: 1-11
        • Veldic M.
        • Kadriu B.
        • Maloku E.
        • Agis-Balboa R.C.
        • Guidotti A.
        • Davis J.M.
        • et al.
        Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder.
        Schizophr Res. 2007; 91: 51-61
        • Ruzicka W.B.
        • Zhubi A.
        • Veldic M.
        • Grayson D.R.
        • Costa E.
        • Guidotti A.
        Selective epigenetic alteration of layer I GABAergic neurons isolated from prefrontal cortex of schizophrenia patients using laser-assisted microdissection.
        Mol Psychiatry. 2007; 4: 385-397
        • Dong E.
        • Gavin D.
        • Chen Y.
        • Davis J.
        Up-regulation of TET1 and down-regulation of APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients.
        Transl Psychiatry. 2012; 2: e159
        • Zhubi A.
        • Chen Y.
        • Dong E.
        • Cook E.H.
        • Guidotti A.
        • Grayson D.R.
        Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum.
        Transl Psychiatry. 2014; 21: e349
        • Grayson D.R.
        • Guidotti A.
        The dynamics of DNA methylation in schizophrenia and related psychiatric disorders.
        Neuropsychopharmacology. 2013; 38: 138-166
        • Abdolmaleky H.M.
        • Cheng K.H.
        • Russo A.
        • Smith C.L.
        • Faraone S.V.
        • 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: 60-66
        • Akbarian S.
        Epigenetics of schizophrenia.
        Curr Top Behav Neurosci. 2010; 4: 611-628
        • Auta J.
        • Smith R.C.
        • Dong E.
        • Tueting P.
        • Sershen H.
        • Boules S.
        • et al.
        DNA-methylation gene network dysregulation in peripheral blood lymphocytes of schizophrenia patients.
        Schizophr Res. 2013; 150: 312-318
        • Gavin D.E.P.
        • Sharma R.P.
        • Chase K.A.
        • Matrisciano F.
        • Dong E.
        • Guidotti A.
        Growth arrest and DNA-damage-inducible, beta (GADD45b)-mediated DNA demethylation in major psychosis.
        Neuropsychopharmacology. 2012; 2: 531-542
        • Thompson R.M.
        • Weickert C.S.
        • Wyatt E.
        • Webster M.J.
        Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders.
        J Psychiatry Neurosci. 2011; 36: 195-203
        • Wong J.
        • Hyde T.M.
        • Cassano H.L.
        • Deep-Soboslay A.
        • Kleinman J.E.
        • Weickert C.S.
        Promoter specific alterations of brain-derived neurotrophic factor mRNA in schizophrenia.
        Neuroscience. 2010; 169: 1071-1084
        • Weickert C.S.
        • Hyde T.M.
        • Lipska B.K.
        • Herman M.M.
        • Weinberger D.R.
        • Kleinman J.E.
        Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia.
        Mol Psychiatry. 2003; 8: 592-610
        • Gavin D.P.
        • Akbarian S.
        Epigenetic and post-transcriptional dysregulation of gene expression in schizophrenia and related disease.
        Neurobiol Dis. 2012; 46: 255-262
        • Ikegame T.
        • Bundo M.
        • Murata Y.
        • Kasai K.
        • Kato T.
        • Iwamoto K.
        DNA methylation of the BDNF gene and its relevance to psychiatric disorders.
        J Hum Genet. 2013; 58: 434-438
        • Autry A.E.
        • Monteggia L.M.
        Brain-derived neurotrophic factor and neuropsychiatric disorders.
        Pharmacol Rev. 2012; 64: 238-258
        • Keller S.
        • Sarchiapone M.
        • Zarrilli F.
        • Ferraro A.
        • Carli V.
        • Sacchetti S.
        • et al.
        Increased BDNF promoter methylation in the Wernicke area of suicide subjects.
        Arch Gen Psychiatry. 2010; 67: 258-267
        • Karpova N.N.
        Role of BDNF epigenetics in activity-dependent neuronal plasticity.
        Neuropharmacology 76(Pt C). 2014; : 709-718
        • Martinowich K.
        • Manji H.
        • Lu B.
        New insights into BDNF function in depression and anxiety.
        Nat Neurosci. 2007; 10: 1089-1093
        • Tadić A.
        • Müller-Engling L.
        • Schlicht K.F.
        • Kotsiari A.
        • Dreimüller N.
        • Kleimann A.
        • et al.
        Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression.
        Mol Psychiatry. 2014; 19: 281-283
        • Stevens H.E.
        • Su T.
        • Yanagawa Y.
        • Vaccarino F.M.
        Prenatal stress delays inhibitory neuron progenitor migration in the developing neocortex.
        Psychoneuroendocrinology. 2013; 38: 509-521
        • Fine R.
        • Zhang J.
        • Stevens H.E.
        Prenatal stress and inhibitory neuron systems: Implications for neuropsychiatric disorders.
        Mol Psychiatry. 2014; 19: 641-651
      1. Negron-Oyarzo I, Neira D, Espinosa N, Fuentealba, Aboitiz F (2014): Prenatal stress produces persistence of remote memory and disrupts functional connectivity in the hippocampal-prefrontal cortex axis [published online ahead of print May 23]. Cereb Cortex.

        • National Research Council
        Guide for the Care and Use of Laboratory Animals..
        The National Academies Press, Washington, DC1996
        • Carboni G.
        • Tueting P.
        • Tremolizzo L.
        • Sugaya I.
        • Davis J.
        • Costa E.
        • Guidotti A.
        Enhanced dizocilpine efficacy in heterozygous reeler mice relates to GABA turnover downregulation.
        Neuropharmacology. 2004; 46: 1070-1081
        • McFarlane H.G.
        • Kusek G.K.
        • Yang M.
        • Phoenix J.L.
        • Bolivar V.J.
        • Crawley J.N.
        Autism-like behavioral phenotypes in BTBR T+tf/J mice.
        Genes Brain Behav. 2008; 7: 152-163
        • Vandesompele J.
        • De Preter K.
        • Pattyn F.
        • Poppe B.
        • Van Roy N.
        • De Paepe A.
        • et al.
        Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes.
        Genome Biol. 2002; 3 (RESEARCH0034)
        • Jin S.G.
        • Wu X.
        • Li A.X.
        • Pfeifer G.P.
        Genomic mapping of 5-hydroxymethylcytosine in the human brain.
        Nucleic Acids Res. 2011; 39: 5015-5024
        • Valinluck V.
        • Tsai H.H.
        • Rogstad D.K.
        • Burdzy A.
        • Bird A.
        • Sowers L.C.
        Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2).
        Nucleic Acids Res. 2004; 32: 4100-4108
        • Dong E.
        • Nelson M.
        • Grayson D.R.
        • Costa E.
        • Guidotti A.
        Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation.
        Proc Natl Acad Sci U S A. 2008; 105: 13614-13619
        • Ma D.K.
        • Jang M.H.
        • Guo J.U.
        • Kitabatake Y.
        • Chang M.L.
        • Pow-Anpongkul N.
        • et al.
        Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis.
        Science. 2009; 323: 1074-1077
        • Aid T.
        • Kazantseva A.
        • Piirsoo M.
        • Palm K.
        • Timmusk T.
        Mouse and rat BDNF gene structure and expression revisited.
        J Neurosci Res. 2007; 85: 525-535
        • Lisman J.E.
        • Coyle J.T.
        • Green R.W.
        • Javitt D.C.
        • Benes F.M.
        • Heckers S.
        • Grace A.A.
        Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia.
        Trends Neurosci. 2008; 31: 234-242
        • Guidotti A.
        • Dong E.
        • Kundakovic M.
        • Satta R.
        • Grayson D.R.
        • Costa E.
        Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling.
        Trends Pharmacol Sci. 2009; 30: 55-60