DNA-Methyltransferase 1 mRNA Is Selectively Overexpressed in Telencephalic GABAergic Interneurons of Schizophrenia Brains

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 1; pp. 348 - 353
• Main Authors: Veldic, M., Caruncho, H. J., Liu, W. S., Davis, J., Satta, R., Grayson, D. R., Guidotti, A., Costa, E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 06.01.2004; National Acad Sciences
• Subjects: Adult; Aged; Antipsychotic agents; Biological Sciences; Brain; Case-Control Studies; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - metabolism; Chromatin; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; Down regulation; Enzymes; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Female; gamma-Aminobutyric Acid - metabolism; Gene Expression; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - metabolism; Humans; In situ hybridization; Interneurons; Interneurons - enzymology; Isoenzymes - genetics; Isoenzymes - metabolism; Male; Mental disorders; Messenger RNA; Methylation; Middle Aged; Nerve Tissue Proteins; Neurons; Promoter Regions, Genetic; Purkinje cells; reelin; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Schizophrenia; Schizophrenia - enzymology; Schizophrenia - genetics; Serine Endopeptidases; Telencephalon - enzymology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2637013100

A down-regulation of reelin and glutamic acid decarboxylase (GAD) 67 mRNAs was detected in γ-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-methyl-transferase 1 expression in telencephalic GABAergic interneurons of SZ patients causes a promoter hypermethylation of reelin and GAD67and 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.