Schizophrenia: One Coat of Many Colors

leads to excessive methylation and hence down regulation of the reelin, GAD67, and other genes, resulting in down regulation of the GABAergic INs (Grayson et al., 2005; Grayson and Guidotti, 2013). The activity of Dnmt is regulated by redox factors at several levels (Hitchler and Domann, 2012; Kang et al., 2012). S-adenosylmethionine (the universal methyl group donor derived from methionine) may also play a role in the chemobiology of schizophrenia. It has been known for 50 years that l-methionine exacerbates the symptoms in chronic schizophrenia (Polin et al., 1961; Antun et al., 1971). A similar result is found in mice treated with excess l-methionine, i.e., hypermethylation of the reelin gene and the resulting down regulation of reelin and GAD expression (Dong et al., 2005). The mice also show decreased spine density in frontal cortex. This effect is prevented by valproate, which is an inhibitor of DNA methylation (Dong et al., 2010). DNA methylation and histone acetylation of the GAD1 gene are heavily influenced by the level of maternal care during the neonatal and preweaning periods (Zhang et al., 2010). These workers showed that pups reared by high grooming/licking (highLG) dams showed enhanced hippocampal GAD1 mRNA expression, decreased cytosine methylation, and increased histone 3-lysine 9 acetylation (H3K9ac) of the GAD1 promoter. DNA methyltransferase 1 expression was significantly higher in the offspring of low-compared with high-LG mothers. Ketamine effects on PV + neurons are prevented by inhibition of DNAmethylation (Behrens et al., 2010).