RESUMO
The neuronal GABAergic mechanisms that mediate the symptomatic beneficial effects elicited by a combination of antipsychotics with valproate (a histone deacetylase inhibitor) in the treatment of psychosis (expressed by schizophrenia or bipolar disorder patients) are unknown. This prompted us to investigate whether the beneficial action of this combination results from a modification of histone tail covalent esterification or is secondary to specific chromatin remodeling. The results suggest that clozapine, or sulpiride associated with valproate, by increasing DNA demethylation with an unknown mechanism, causes a chromatin remodeling that brings about a beneficial change in the epigenetic GABAergic dysfunction typical of schizophrenia and bipolar disorder patients.
Assuntos
Metilação de DNA/genética , Epigênese Genética , Regiões Promotoras Genéticas/genética , Esquizofrenia/genética , Ácido gama-Aminobutírico/metabolismo , Animais , Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Glutamato Descarboxilase/genética , Humanos , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteína Reelina , Esquizofrenia/tratamento farmacológico , Serina Endopeptidases/genéticaRESUMO
In this review, we discuss changes in the regulation of gene expression in the central nervous system (CNS) associated with DNA (cytosine-5) methylation, chromatin remodeling and post-translational covalent modifications of histones. During brain development, abnormal intrinsic or extrinsic cues may compromise epigenetic processes regulating neural stem cell proliferation and differentiation and thus directly or indirectly could contribute to altered epiphenotypes leading to psychiatric disorders. These mechanisms, that include chromatin remodeling and reversible changes in promoter methylation patterns, are largely expressed by terminally differentiated cortical GABAergic neurons. These neurons are unique among various brain cell subtypes because they express high levels of DNA-methyltransferase-1 (DNMT1). Moreover, DNMT1 expression is further increased in schizophrenia (SZ) and bipolar (BP) disorder brains. To unravel how this pathological DNMT1 overexpression induces GABAergic neuronal dysfunction in SZ and in other psychoses, we report on how alterations in methylation modify the expression of susceptible vulnerability genes such as reelin or GAD67 in these neurons. The results encourage the view that promoter hypermethylation in GABAergic neurons that occurs in SZ represents a testable target for novel therapeutic strategies to treat this disorder.
Assuntos
Córtex Cerebral/fisiopatologia , DNA (Citosina-5-)-Metiltransferases/genética , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Transtornos Psicóticos/genética , Esquizofrenia/genética , Ácido gama-Aminobutírico/fisiologia , Transtorno Bipolar/enzimologia , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Histonas/genética , Histonas/metabolismo , Humanos , Transtornos Psicóticos/enzimologia , Transtornos Psicóticos/patologia , Proteína Reelina , Esquizofrenia/patologiaRESUMO
Prefrontal cortex (Brodmann's area 9) levels of the methyl donor S-adenosyl methionine were increased by about two-fold in schizophrenia and bipolar disorder patients, but not in unipolar depressed patients compared with nonpsychiatric subjects from the Stanley Foundation Neuropathology Consortium (Bethesda, Maryland, USA). Neither age, brain weight and pH, hemisphere, post-mortem interval, disease onset/duration, nor cumulative dose of fluphenazine affected S-adenosyl methionine content. In schizophrenia and bipolar disorder patients, the increase of S-adenosyl methionine is associated with an overexpression of DNA methyltransferase-1 mRNA in Brodmann's area 9 GABAergic neurons. Hence, the increased expression of S-adenosyl methionine and DNA methyltransferase-1 may contribute to promoter cytosine 5-methylation and to downregulation of the expression of mRNAs encoding for reelin and GAD67 in cortical GABAergic neurons of schizhophrenia and bipolar disorder patients.
