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Schizophr Res. 2015 Sep;167(1-3):28-34. doi: 10.1016/j.schres.2014.10.020. Epub 2014 Oct 31.

Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia.

Author information

1
Departments of Psychiatry and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
2
Departments of Psychiatry and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States. Electronic address: schahram.akbarian@mssm.edu.

Abstract

Expression of GAD1 GABA synthesis enzyme is highly regulated by neuronal activity and reaches mature levels in the prefrontal cortex not before adolescence. A significant portion of cases diagnosed with schizophrenia show deficits in GAD1 RNA and protein levels in multiple areas of adult cerebral cortex, possibly reflecting molecular or cellular defects in subtypes of GABAergic interneurons essential for network synchronization and cognition. Here, we review 20years of progress towards a better understanding of disease-related regulation of GAD1 gene expression. For example, deficits in cortical GAD1 RNA in some cases of schizophrenia are associated with changes in the epigenetic architecture of the promoter, affecting DNA methylation patterns and nucleosomal histone modifications. These localized chromatin defects at the 5' end of GAD1 are superimposed by disordered locus-specific chromosomal conformations, including weakening of long-range promoter-enhancer loopings and physical disconnection of GAD1 core promoter sequences from cis-regulatory elements positioned 50 kilobases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including developmentally regulated higher order chromatin compromised by the disease process, together with exploration of locus-specific epigenetic interventions in animal models, could pave the way for future treatments of psychosis and schizophrenia.

KEYWORDS:

Epigenetics; GABA; GAD1; Prefrontal cortex; Transcription factors

PMID:
25458568
PMCID:
PMC4417100
DOI:
10.1016/j.schres.2014.10.020
[Indexed for MEDLINE]
Free PMC Article

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