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Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by
Erbo Dong1, Svetlana G Dzitoyeva1, Francesco Matrisciano1
1Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
Insights
Prenatal stress in mice causes behavioral changes and epigenetic alterations in brain genes, mirroring schizophrenia in humans. This animal model offers insights into neurodevelopmental disorders and their molecular underpinnings.
Area of Science:
- Neuroscience
- Epigenetics
- Developmental Psychology
Background:
- Prenatal stress (PRS) is a risk factor for neurodevelopmental disorders like schizophrenia (SZ).
- PRS may induce epigenetic changes in GABAergic and glutamatergic genes, including brain-derived neurotrophic factor (BDNF).
Purpose of the Study:
- To investigate the long-term behavioral and molecular effects of PRS in adult offspring.
- To examine epigenetic modifications in key chromatin remodeling factors and BDNF expression.
Main Methods:
- Adult offspring of PRS mice were studied for behavioral abnormalities.
- Expression of DNA methyltransferases, ten-eleven-translocation hydroxylases, methyl CpG binding protein 2, histone modifiers, and BDNF was measured.
- DNA methylation at BDNF gene regulatory regions was analyzed.
Main Results:
- PRS offspring exhibited SZ-like behaviors and molecular changes, including increased DNA methyltransferase 1 and ten-eleven-translocation hydroxylase 1.
- A significant decrease in BDNF mRNA variants was observed, with altered DNA methylation at its regulatory regions.
- BDNF transcript levels correlated positively with social approach behavior.
Conclusions:
- PRS mice display an epigenetic signature similar to patients with psychosis.
- This animal model is valuable for studying the molecular and behavioral aspects of schizophrenia.
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.
