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DNA Methylation in Animal Models of Psychosis.

ABSTRACT: Schizophrenia (SZ) is a debilitating disease that impacts 1% of the population worldwide. Association studies have shown that inherited genetic mutations account for a portion of disease risk. However, environmental factors play an important role in the pathophysiology of the disease by altering cellular epigenetic marks at the level of chromatin. Postmortem brain studies of SZ subjects suggest that the dynamic equilibrium between DNA methylation and demethylation network components is disrupted at the level of individual SZ target genes. Herein, we review the role of DNA methylation and demethylation in the context of what is currently known regarding SZ. Furthermore, we describe the deficits that accompany two mouse models of SZ. The chronic methionine mouse model of SZ is predicated on the administration of methionine to SZ patients and controls in the context of clinical studies that were carried out during the 1960s and 1970s. The prenatal restraint stress model of SZ is based on a prolonged stress paradigm administered to pregnant dams during gestation days 7-21. The adult offspring of these dams show various behavioral and biochemical deficits in adulthood. Both models are epigenetic in origin and mimic the positive and negative symptoms, as well as the cognitive endophenotypes commonly observed in SZ patients. We also discuss the utility of typical and atypical antipsychotic drugs in alleviating these symptoms in each model.

SUBMITTER: Grayson DR

PROVIDER: S-EPMC7939130 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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DNA Methylation in Animal Models of Psychosis.

Grayson Dennis R DR Guidotti Alessandro A

Progress in molecular biology and translational science 20180330

Schizophrenia (SZ) is a debilitating disease that impacts 1% of the population worldwide. Association studies have shown that inherited genetic mutations account for a portion of disease risk. However, environmental factors play an important role in the pathophysiology of the disease by altering cellular epigenetic marks at the level of chromatin. Postmortem brain studies of SZ subjects suggest that the dynamic equilibrium between DNA methylation and demethylation network components is disrupted ...[more]

PMID: 29933947

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Project description:BACKGROUND:The dopamine (DA) hypothesis of schizophrenia proposes the mental illness is caused by excessive transmission of dopamine in selected brain regions. Multiple lines of evidence, including blockage of dopamine receptors by antipsychotic drugs that are used to treat schizophrenia, support the hypothesis. However, the dopamine D2 receptor (DRD2) blockade cannot explain some important aspects of the therapeutic effect of antipsychotic drugs. In this study, we hypothesized that antipsychotic drugs could affect the transcription of genes in the DA pathway by altering their epigenetic profile. METHODS:To test this hypothesis, we examined the effect of olanzapine, a commonly used atypical antipsychotic drug, on the DNA methylation status of genes from DA neurotransmission in the brain and liver of rats. Genomic DNA isolated from hippocampus, cerebellum, and liver of olanzapine treated (n?=?2) and control (n?=?2) rats were analyzed using rat specific methylation arrays. RESULTS:Our results show that olanzapine causes methylation changes in genes encoding for DA receptors (dopamine D1 receptor, dopamine D2 receptor and dopamine D5 receptor), a DA transporter (solute carrier family 18 member 2), a DA synthesis (differential display clone 8), and a DA metabolism (catechol-O-methyltransferase). We assessed a total of 40 genes in the DA pathway and found 19 to be differentially methylated between olanzapine treated and control rats. Most (17/19) genes showed an increase in methylation, in their promoter regions with in silico analysis strongly indicating a functional potential to suppress transcription in the brain. CONCLUSION:Our results suggest that chronic olanzapine may reduce DA activity by altering gene methylation. It may also explain the delayed therapeutic effect of antipsychotics, which occurs despite rapid dopamine blockade. Furthermore, given the common nature of epigenetic variation, this lends insight into the differential therapeutic response of psychotic patients who display adequate blockage of dopamine receptors.

Dataset Information

DNA Methylation in Animal Models of Psychosis.

Publications

DNA Methylation in Animal Models of Psychosis.

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