It is becoming increasingly clear that a dysfunction of the GABAergic/glutamatergic network in telencephalic brain structures may be the pathogenetic mechanism underlying psychotic symptoms in schizophrenia (SZ) and bipolar (BP) disorder patients. Data obtained in Costa’s laboratory (1996–2009) suggest that this dysfunction may be mediated primarily by a downregulation in the expression of GABAergic genes (e.g., glutamic acid decarboxylase67 [GAD67] and reelin) associated with DNA-methyltransferase (DNMT)-dependent hypermethylation of their promoters. A pharmacological strategy to reduce the hypermethylation of GABAergic promoters is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that induce DNA-demethylation when administered at doses that facilitate chromatin remodeling. The benefits elicited by combining VPA with antipsychotics in the treatment of BP disorder suggest that an investigation of the epigenetic interaction of these drugs is warranted. Our studies in mice suggest that when associated with VPA, clinically relevant doses of clozapine elicit a synergistic potentiation of VPA-induced GABAergic promoter demethylation. Olanzapine and quetiapine (two clozapine congeners) also facilitate chromatin remodeling but at doses higher than used clinically, whereas haloperidol and risperidone are inactive. Hence, the synergistic potentiation of VPA’s action on chromatin remodeling by clozapine appears to be a unique property of the dibenzepines and is independent of their action on catecholamine or serotonin receptors. By activating DNA-demethylation, the association of clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be considered a promising treatment strategy for normalizing GABAergic promoter hypermethylation and the GABAergic gene expression downregulation detected in the postmortem brain of SZ and BP disorder patients.

Aberrant neocortical DNA methylation has been suggested to be a pathophysiological contributor to psychotic disorders. Recently, a growth arrest and DNA-damage-inducible, beta (GADD45b) protein-coordinated DNA demethylation pathway, utilizing cytidine deaminases and thymidine glycosylases, has been identified in the brain. We measured expression of several members of this pathway in parietal cortical samples from the Stanley Foundation Neuropathology Consortium (SFNC) cohort. We find an increase in GADD45b mRNA and protein in patients with psychosis. In immunohistochemistry experiments using samples from the Harvard Brain Tissue Resource Center, we report an increased number of GADD45b-stained cells in prefrontal cortical layers II, III, and V in psychotic patients. Brain-derived neurotrophic factor IX (BDNF IXabcd) was selected as a readout gene to determine the effects of GADD45b expression and promoter binding. We find that there is less GADD45b binding to the BDNF IXabcd promoter in psychotic subjects. Further, there is reduced BDNF IXabcd mRNA expression, and an increase in 5-methylcytosine and 5-hydroxymethylcytosine at its promoter. On the basis of these results, we conclude that GADD45b may be increased in psychosis compensatory to its inability to access gene promoter regions.

Histone deactylase enzymes are responsible for the deacetylation of histone tails, and consequently influence gene regulation through their ability to modify chromatin structure surrounding promoter regions. We analyzed the microarray collection of the National Brain Databank to investigate differential expression of these enzymes in the prefrontal cortices of control, schizophrenia and bipolar subjects. HDAC1 expression levels were significantly higher in schizophrenia versus normal subjects. The mRNA expression level of an epigenetically regulated gene GAD67 was strongly and negatively correlated with the mRNA expression levels of HDAC1, HDAC3 and HDAC4 levels. These findings provide additional support for the proposal that epigenetic factors are operative in the brain pathology of patients with schizophrenia.

Increasing evidence suggests that epigenetic dysfunction may account for the alteration of gene transcription present in neuropsychiatric disorders such as schizophrenia (SZ), bipolar disorder (BP) and autism. Here, we studied the expression of the ten-eleven translocation (TET) gene family and activation-induced deaminase/apolipoprotein B mRNA-editing enzymes (AID/APOBEC) in the inferior parietal lobule (IPL) (BA39-40) and the cerebellum of psychotic (PSY) patients, depressed (DEP) patients and nonpsychiatric (CTR) subjects obtained from the Stanley Foundation Neuropathology Consortium Medical Research Institute. These two sets of enzymes have a critical role in the active DNA demethylation pathway. The results show that TET1, but not TET2 and TET3, mRNA and protein expression was increased (two- to threefold) in the IPL of the PSY patients compared with the CTR subjects. TET1 mRNA showed no change in the cerebellum. Consistent with the increase of TET1, the level of 5-hydroxymethylcytosine (5hmC) was elevated in the IPL of PSY patients but not in the other groups. Moreover, higher 5hmC levels were detected at the glutamic acid decarboxylase67 (GAD67) promoter only in the PSY group. This increase was inversely related to the decrease of GAD67 mRNA expression. Of 11 DNA deaminases measured, APOBEC3A mRNA was significantly decreased in the PSY and DEP patients, while APOBEC3C was decreased only in PSY patients. The other APOBEC mRNA studied failed to change. Increased TET1 and decreased APOBEC3A and APOBEC3C found in this study highlight the possible role of altered DNA demethylation mechanisms in the pathophysiology of psychosis.

During the last 20 years, new and exciting roles for glial cells in brain development have been described. Moreover, several recent studies implicated glial cells in the pathogenesis of neurodevelopmental disorders including Down syndrome, Fragile X syndrome, Rett Syndrome, Autism Spectrum Disorders, and Fetal Alcohol Spectrum Disorders (FASD). Abnormalities in glial cell development and proliferation and increased glial cell apoptosis contribute to the adverse effects of ethanol on the developing brain and it is becoming apparent that the effects of fetal alcohol are due, at least in part, to effects on glial cells affecting their ability to modulate neuronal development and function. The three major classes of glial cells, astrocytes, oligodendrocytes, and microglia as well as their precursors are affected by ethanol during brain development. Alterations in glial cell functions by ethanol dramatically affect neuronal development, survival, and function and ultimately impair the development of the proper brain architecture and connectivity. For instance, ethanol inhibits astrocyte-mediated neuritogenesis and oligodendrocyte development, survival and myelination; furthermore, ethanol induces microglia activation and oxidative stress leading to the exacerbation of ethanol-induced neuronal cell death. This review article describes the most significant recent findings pertaining the effects of ethanol on glial cells and their significance in the pathophysiology of FASD and other neurodevelopmental disorders.