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Critical Reviews™ in Neurobiology

ISSN for PRINT: 0892-0915

Institutional price:	$649.00
Issues per year:	4

Best Paper Award Selection - Editorial Board Site

2003, Volume15

88 pages

DOI: 10.1615/CritRevNeurobiol.v15.i2

Issue price - $110.00

GABAergic Cortical Neuron Chromatin as a Putative Target to Treat Schizophrenia Vulnerability

Erminio Costa
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor St., Chicago IL 60612, USA

Dennis R. Grayson
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA

Colin P. Mitchell
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA

Lucio Tremolizzo
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA

Marin Veldic
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA

Alessandro Guidotti
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA

ABSTRACT

Inhibitory GABAergic interneurons of prefrontal cortex (PFC) appear to play an important role in the regulation of intermittent pyramidal neuron columnary firing and in the neuronal plasticity that mediate cognitive functions. In schizophrenia (SZ), cognitive defects and dysfunctions in pyramidal neuronal columnary firing appear to depend on abnormalities of GABAergic neurons. These abnormalities include a decrease of GAD₆₇ and reelin expression, which result in a reduction of cortical inhibitory input to spine postsynaptic densities as a result of the decrease of GABA concentration at the synaptic cleft, and of neurotrophic stimuli as a result of the decrease of reelin secreted into the extracellular matrix. Our studies show that alterations in chromatin remodeling related to a selective upregulation of DNA-5-cytosine methyltransferase (DNMT) expression in GABAergic neurons of SZ PFC may induce a hypermethylation of reelin and GAD₆₇ promoter CpG islands, which downregulates their expression. In addition, we report preliminary evidence suggesting that by targeting this chromatin-remodeling deficit with inhibitors of histone deacetylases (HDAC), it may be possible to reduce the DNMT upregulation via a covalent modification of nucleosomal histone tails, underscoring the possibility that by addressing a chromatin remodeling deficit, one may treat psychiatric disorders.