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Science 327 (5962): 213-216

Copyright © 2010 by the American Association for the Advancement of Science

Essential Role of the Histone Methyltransferase G9a in Cocaine-Induced Plasticity

Ian Maze,1 Herbert E. Covington, III,1 David M. Dietz,1 Quincey LaPlant,1,2 William Renthal,2 Scott J. Russo,1 Max Mechanic,2 Ezekiell Mouzon,1 Rachael L. Neve,3 Stephen J. Haggarty,4,5 Yanhua Ren,1 Srihari C. Sampath,6 Yasmin L. Hurd,1 Paul Greengard,7 Alexander Tarakhovsky,6 Anne Schaefer,7 Eric J. Nestler1,*

Abstract: Cocaine-induced alterations in gene expression cause changes in neuronal morphology and behavior that may underlie cocaine addiction. In mice, we identified an essential role for histone 3 lysine 9 (H3K9) dimethylation and the lysine dimethyltransferase G9a in cocaine-induced structural and behavioral plasticity. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region, which was regulated by the cocaine-induced transcription factor {triangleup}FosB. Using conditional mutagenesis and viral-mediated gene transfer, we found that G9a down-regulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.

1 Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
2 Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3 Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
4 Psychiatric and Neurodevelopmental Genetics Unit and Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
5 Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
6 Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY, USA.
7 Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.

* To whom correspondence should be addressed. E-mail: eric.nestler{at}mssm.edu


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