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Epigenetic Regulation of GABAergic Targets in Psychiatry

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Brain, Behavior and Epigenetics

Part of the book series: Epigenetics and Human Health ((EHH))

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Abstract

One of the more consistent findings observed in post mortem tissue from schizophrenia (SZ) patients is that the genes encoding reelin and glutamate decarboxylase 67 (GAD67 or GAD1) are downregulated in cortex and other brain regions. Reelin is important for cortical migration during development and for synaptic plasticity and memory acquisition in the adult. GAD1 is one of two enzymes that synthesize the inhibitory neurotransmitter GABA in the central nervous system. Those neurons that make GABA are GABAergic and they serve a role in dampening excitatory neurotransmission throughout the brain. In addition, reports also show that NMDA receptor subunit expression and excitatory neurotransmission are reduced in cortical GABA neurons of SZ patients. Conditional knockout mice in which the NR1 subunit of the NMDA receptor is selectively reduced in GABA neurons of the brain show a downregulation of GAD67 and parvalbumin (PV) mRNAs and also exhibit behaviors characteristic of SZ. These findings allow us to conceptually integrate two major schools of thought regarding the neurotransmitter deficit responsible for the symptoms of this psychiatric disorder. That is, if reduced glutamatergic neurotransmission occurs on GABAergic interneurons, the net effect would be reduced GABA output impacting the neuronal synchronization of pyramidal cell firing. Since it has also been shown that in GABAergic neurons, the mRNA encoding DNA methyltransferase 1 (DNMT1) is increased in SZ patients, this and other data suggest an epigenetic mechanism by which certain genes may be selectively downregulated contributing to SZ symptomatology. We propose that enzymes that methylate DNA and selectively reduce gene expression are hyperactive in patients with SZ and that this may be related to the pathogenesis of the disease. Here, we discuss these concepts in more detail and present our integrated view of synaptic transmission in SZ.

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Acknowledgments

We would like to dedicate this work to the memory of our friend and colleague, Dr. Erminio Costa, University of Illinois at Chicago, who died November 28, 2009.

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Authors and Affiliations

  1. Department of Psychiatry, The Psychiatric Institute, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St, Chicago, IL, 60612, USA

    Dennis R. Grayson, Marija Kundakovic, Ying Chen, Erbo Dong & Alessandro Guidotti

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  1. Dennis R. Grayson
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  2. Marija Kundakovic
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  3. Ying Chen
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  4. Erbo Dong
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  5. Alessandro Guidotti
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Correspondence to Dennis R. Grayson .

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Editors and Affiliations

  1. , The Krembil Family Epigenetics Laborator, Centre for Addiction and Mental Health, College Street 250, Toronto, M5T 1R8, Ontario, Canada

    Arturas Petronis

  2. , Institute of Psychiatry, King's College London, De Crispigny Park, London, SE5 8AF, United Kingdom

    Jonathan Mill

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Grayson, D.R., Kundakovic, M., Chen, Y., Dong, E., Guidotti, A. (2011). Epigenetic Regulation of GABAergic Targets in Psychiatry. In: Petronis, A., Mill, J. (eds) Brain, Behavior and Epigenetics. Epigenetics and Human Health. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17426-1_2

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