GABAergic promoter hypermethylation as a model to study the neurochemistry of schizophrenia vulnerability.

Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA.
Expert Review of Neurotherapeutics (Impact Factor: 2.96). 02/2009; 9(1):87-98. DOI: 10.1586/14737175.9.1.87
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: Metabolomics research has the potential to provide biomarkers for the detection of disease, for subtyping complex disease populations, for monitoring disease progression and therapy, and for defining new molecular targets for therapeutic intervention. These potentials are far from being realized due to a number of technical, conceptual, financial and bioinformatics issues. Mass spectrometry provides analytical platforms that address the technical barriers to success in metabolomics research; however, the limited commercial availability of analytical and stable isotope standards has created a bottleneck for the absolute quantitation of a number of metabolites. Conceptual and financial factors contribute to the generation of statistically under-powered clinical studies, while bioinformatics issues result in the publication of a large number of unidentified metabolites. The path forward in this field involves targeted metabolomics analyses of large control and patient populations to define both the normal range of a defined metabolite and the potential heterogeneity (eg bimodal) in complex patient populations. This approach requires that metabolomics research groups, in addition to developing a number of analytical platforms, build sufficient chemistry resources to supply the analytical standards required for absolute metabolite quantitation. Examples of metabolomics evaluations of sulfur amino acid metabolism in psychiatry, neurology, and neuro-oncology, and lipidomics in neurology will be reviewed.Neuropsychopharmacology accepted article preview online, 11 July 2013. doi:10.1038/npp.2013.167.
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    ABSTRACT: Schizophrenia (SCZ) is a severe psychiatric disorder, which lacks a unifying neuropathology. However, reproducible molecular alterations exist, including RNA expression changes affecting GABAergic and other neuronal signaling in cerebral cortex, myelination, and other cellular functions. Yet, for the large majority of RNAs altered in the SCZ brain, the underlying transcriptional and post-transcriptional disease-associated mechanisms remain unclear. Here, we provide an update on epigenetic regulators of gene expression that are potentially affected in some cases with SCZ, including DNA cytosine methylation, histone modifications and histone variants, and chromosomal loop formations facilitating long-range interactions of gene promoters with distal enhancer elements. Exploration of chromatin structure and function, in combination with transcriptome and genome sequencing, is likely to critically advance insight into the molecular mechanisms of disease in specific cases with SCZ.
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    ABSTRACT: Cocaine exposure induces changes in the expression of numerous genes, in part through epigenetic modifications. We have initially shown that cocaine increases the expression of the chromatin remodeling protein methyl-CpG binding protein 2 (MeCP2) and characterized the protein phosphatase-1Cβ (PP1Cβ) gene, as repressed by passive i.p. cocaine injections through a Mecp2-mediated mechanism involving de novo DNA methylation. Both proteins being involved in learning and memory processes, we investigated whether voluntary cocaine administration would similarly affect their expression using an operant self-administration paradigm. Passive and voluntary i.v. cocaine intake was found to induce Mecp2 and to repress PP1Cβ in the prefrontal cortex and the caudate putamen. This observation is consistent with the role of Mecp2 acting as a transcriptional repressor of PP1Cβ and shows that passive intake was sufficient to alter their expression. Surprisingly, striking differences were observed under the same conditions in food-restricted rats tested for food pellet delivery. In the prefrontal cortex and throughout the striatum, both proteins were induced by food operant conditioning, but remained unaffected by passive food delivery. Although cocaine and food activate a common reward circuit, changes observed in the expression of other genes such as reelin and GAD67 provide new insights into molecular mechanisms differentiating neuroadaptations triggered by each reinforcer. The identification of hitherto unknown genes differentially regulated by drugs of abuse and a natural reinforcer should improve our understanding of how two rewarding stimuli differ in their ability to drive behavior.

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