Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice

Erbo Dong*, Svetlana G. Dzitoyeva, Francesco Matrisciano, Patricia Tueting, Dennis R. Grayson, Alessandro Guidotti

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Background 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). Methods 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. Results 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. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)589-596
Number of pages8
JournalBiological psychiatry
Volume77
Issue number6
DOIs
StatePublished - Mar 15 2015

Keywords

  • BDNF
  • DNA methylation
  • DNMT
  • Prenatal stress
  • Schizophrenia
  • TET

ASJC Scopus subject areas

  • Biological Psychiatry

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