DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains

Abstract

A down-regulation of reelin and glutamic acid decarboxylase (GAD) 67 mRNAs was detected in ␥-aminobutyric acid (GABA)ergic cortical interneurons of schizophrenia (SZ) postmortem brains (10), suggesting that the availability of GABA and reelin may be decreased in SZ cortex. In situ hybridization of the mRNA encoding for DNA-methyltransferase 1, which catalyzes the methylation of promoter CpG islands, shows that the expression of this mRNA is increased in cortical GABAergic interneurons but not in pyramidal neurons of SZ brains. Counts of reelin mRNA-positive neurons in Brodmann's area 10 of either nonpsychiatric subjects or SZ patients show that the expression of reelin mRNA is decreased in layer-I, -II, and -IV GABAergic interneurons of SZ patients. These findings are consistent with the hypothesis that the increase of DNA-methyltransferase 1 expression in telencephalic GABAergic interneurons of SZ patients causes a promoter hypermethylation of reelin and GAD 67 and perhaps of other genes expressed in these interneurons. It is difficult to decide whether this dysfunction of GABAergic neurons detected in SZ is responsible for this disease or is a consequence of this disorder. Although at present we cannot differentiate between these two alternatives, it is important to consider that so far a molecular pathology of cortical GABAergic neurons appears to be the most consistent finding associated with SZ morbidity.

Histone deacetylases 1 and 2 are expressed at distinct stages of neuro‐glial development

“…The development and function of the nervous system appears to be particularly sensitive to disruptions in epigenetic gene regulation, leading to syndromes associated with mental retardation (reviewed in Egger et al, 2004), as well as complex psychiatric disorders such as schizophrenia (Veldic et al, 2004;Grayson et al, 2005). The nervous system is unique in the remarkably complex patterning of the brain that must be established, while still maintaining a large degree of plasticity in order for the brain to respond to a changing environment.…”

Reelin glycoprotein: structure, biology and roles in health and disease

“…64 These authors suggest that targeting this deficit with inhibitors of histone deacetylases (HDAC), may reduce the DNMT upregulation via covalent modification of nucleosomal histone tails, potentially upregulating Reelin expression in schizophrenic brain. 64,66 Indeed, Veldic et al 67 have recently shown that mRNA for DNA-methyltransferase 1, which catalyzes the methylation of promoter CpG islands, is increased in cortical GABAergic interneurons but not in pyramidal neurons of schizophrenic brains. Despite these biochemical findings, two recent reports fail to report any association between Reln gene polymorphisms and schizophrenia.…”

CpG Methylation in Neurons: Message, Memory, or Mask?

“…The expression of Dnmt3a is observed from late embryogenesis (E10) to adulthood with a peak during the early postnatal period; its expression declines to lower but detectable levels in the adult brain (Feng et al, 2005) with a reported biphasic increase in older humans (Siegmund et al, 2007). This nonconstitutive and regulated expression is supported by the observation that DNMT1 seems more highly expressed in the 'interneurons' of the cortex (GABA interneurons in the cerebral cortex, and granular cells in the cerebellar cortex) than the 'output' neurons, that is, pyramidal or Purkinje cells respectively (Veldic et al, 2004).…”

“…Interestingly, several studies have reported higher DNMT1 mRNA expression in schizophrenia post-mortem cortical and striatal GABAergic neurons (Veldic et al, 2004. DNMT1 expression was negatively correlated with schizophrenia candidate gene expression.…”

“…Nonetheless, there is clear indication of active and nonconstitutive regulation of expression of these enzymes in the brain, across the lifespan and possibly across neuroanatomical regions as well. For example, there is evidence for a robust expression in neurons and perhaps oligodendrocytes, but not in astroglia (Feng et al, 2005;Veldic et al, 2004). In the adult human post-mortem brain, both DNMT1 and DNMT3a are differentially expressed across the layers of the cortex and appear specifically in GABAergic interneurons and less so in pyramidal cells (Veldic et al, 2004Siegmund et al, 2007).…”