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One Carbon Metabolism and DNA Methylation Enrichment in Subjects with Alcohol Use Disorders

DNA methylation is an important epigenetic mark that plays a prominent role in regulating gene expression in mature adult brain. Recent studies in the cerebellum and frontal cortex of Alcohol Use Disorder subjects have shown altered epigenetic regulation of selected genes unique to each brain region. Data from both brain regions supports the hypothesis that aberrant DNA methylation pathways may be involved in the pathophysiology of alcoholism.

Epigenetic mechanisms Operative in Psychotic Disorders

As part of our ongoing studies on the etiopathogenesis of schizophrenia and psychosis-related disorders, we have developed an animal model that mimics some of the behavioral and molecular endophenotypes associated with these disorders. The adult offspring (PRS mice) of prenatally-stressed dams exhibit deficits in selected behaviors such as pre-pulse inhibition to startle, social interaction, fear conditioning and an increase in stereotyped behaviors. In addition, the brains of these mice show increased mRNA and protein corresponding to DNA methyltransferases 1 and 3a, as well as, decreased levels of schizophrenia-related mRNAs. The behavioral and molecular endophenotypes of PRS mice are reminiscent of the behvavioral and molecular endophenotypes associated with SZ.

Chronic Alcohol Exposure Differentially Alters the Levels of S-Adenosyl Methionine (SAM) and S-Adenosyl Homocysteine in the Rat Brain

Chronic alcohol exposure leads to behavioral changes, as well as, decreased expression of genes associated with synaptic plasticity. In this project, we treat rats chronically with alcohol and also subject a group of these to alcohol withdrawal. We find that chronic alcohol administration decreases the levels of SAM and the SAM to SAH ratio by altering the expression of several enzymes associated with SAM biosynthesis and metabolism. Interestingly, the changes in these enzymes that occur in during chronic administration, return to near normal levels following withdrawal. Our results indicate that an increase in the methylation index (SAM/SAH ratio) in the brains of treated animals implicates alterations in one carbon metabolism in the pathophysiology of alcoholism.