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: 2.83). 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.


Available from: Dennis Robert Grayson, Apr 20, 2015
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    ABSTRACT: Background: Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of autism. The metabolic pathology of autism is relatively unexplored although metabolic imbalance is implicated in the pathogenesis of multiple other neurobehavioral disorders. An abnormal accumulation or deficit of specific metabolites in a defined pathway can provide clues into relevant candidate genes and/or environmental exposures. In addition, the identification of precursor-product metabolite imbalance can inform targeted intervention strategies to restore metabolic balance and potentially improve symptoms of autism. We have investigated metabolic pathways essential for cellular methylation and antioxidant capacity and the functional impact of metabolic imbalance on genome-wide DNA hypomethylation and protein/DNA oxidative damage in children with autism. These metabolic pathways regulate the distribution of precursors for DNA synthesis (proliferation), DNA methylation (epigenetic regulation of gene expression) and glutathione synthesis (redox/antioxidant defense capacity). Previously, we reported that the metabolic profile of many children with autism is consistent with reduced methylation capacity and a more oxidized microenvironment. Objectives: To determine whether methylation and antioxidant metabolic profile differs between case children, unaffected siblings, and age-matched control children and to determine whether the metabolic imbalance is accompanied by DNA hypomethylation and protein/DNA oxidative damage. Methods: Subjects included 162 children, ages 3-10, who were participants in the autism IMAGE study (Integrated Metabolic And Genomic Endeavor) at Arkansas Children’s Hospital Research Institute. The IMAGE cohort is comprised of 162 children including of 68 case children, 54 age-matched controls and 40 unaffected siblings. Children with autistic disorder were diagnosed using DSM-IV (299.0), ADOS and/or CARS >30. Fasting plasma samples were analyzed for folate-dependent transmethylation and transsulfuration metabolites and 3-nitrotyrosine (oxidized protein derivative) using HPLC with electrochemical detection. Genome-wide DNA methylation (as %5-methylcytosine) and the oxidized DNA adduct 8-oxo-deoxyguanine were quantified with Dionex HPLC-UV system coupled to an electrospray ionization (ESI) tandem mass spectrometer. Results: In a pair-wise comparison, the overall metabolic profile of the unaffected siblings differed significantly from their autistic siblings but was not different from unrelated control children. In addition, we report new evidence of genome-wide DNA hypomethylation (epigenetic dysregulation) and oxidative protein/DNA damage in children with autism that was not present in their paired siblings or in unaffected control children. Conclusions: These data indicate that the deficit in antioxidant and methylation capacity is autism-specific and is associated with DNA hypomethylation (epigenetic dysregulation) and oxidative damage. Further, these results suggest a plausible mechanism by which environmental stressors might modulate the genetic predisposition to autism. Acknowledgement: This research was supported with funding from the National Institute of Child Health and Development (RO1 HD051873; SJJ) and Department of Defense (AS073218P1; SJJ)
    International Meeting for Autism Research 2011; 05/2011
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    The International Journal of Neuropsychopharmacology 06/2014; 17(12):1-14. DOI:10.1017/S1461145714000972 · 5.26 Impact Factor
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    Clinical Psychopharmacology and Neuroscience 08/2014; 12(2):94-110. DOI:10.9758/cpn.2014.12.2.94