Prefrontal cortex (RFC) GABAergic interneurons are a major target for the molecular pathology associated with schizophrenia (SZ) morbidity; their alteration may contribute to the reduction of cortical neuropil, which is an important component of SZ pathophysiology. Cortical GABAergic neurons participate in the orchestration of cortical pyramidal neuron population firing via the release of GABA on GABAA and GABAB receptors and modulate dendritic spine plasticity via the translation of spine resident mRNAs facilitated by the GABAergic neuron release of reelin acting on integrin receptors located on dendritic spine postsynaptic densities. In SZ cortical GABAergic neurons, the synthesis of GABA and reelin is reduced because of a downregulation in GAQ67 and reelin mRNA expressions. Very probably this is due to an increased expression in GABAergic neurons of DNA-(cytosine 5)-methyltransferase1 (DNMT1) that contributes to the epigenetic hypermethylation of CpG islands and promoters expressed in reelin and GAD67 genes and to the consequent decreased synthesis of these two gene transcripts. Thus, we hypothesize that downregulation of GABAergic function due to an epigenetic mechanism may be an important primary process operative in SZ morbidity. We will study whether: 1) in addition to BA9 and BA10 GABAergic neurons, DNMT1 is coexpressed with reelin and GAD67, in the GABAergic neurons of the occipital cortex and caudate nucleus; 2) in every GABAergic neuron, the increase of DNMT1 expression coincides with a decrease of reelin and GAD67 expression; 3) the increase of DNMT1 and the decrease of reelin and GAD67 expression also extend to brains of bipolar disorder patients; 4) DNMT1 establishes a partnership with complexes including histone deacetylases and histone methylases, two prominent enzymes to regulate the code whereby histones control accessibility of transcription factors or DNMT1 to targeted regulatory sites in gene promoters. A better understanding of how epigenetic mechanisms can regulate reelin and GAD67 gene transcription may allow the discovery of new drug targets that can reprogram transcription and perhaps modify pathologies related to epigenetically-induced downregulation of gene expression in SZ. ? ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Meinecke, Douglas L
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University of Illinois at Chicago
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