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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 Maze1, Herbert E. Covington, III1, David M. Dietz1, Quincey LaPlant1,2, William Renthal2, Scott J. Russo1, Max Mechanic2, Ezekiell Mouzon1, Rachael L. Neve3, Stephen J. Haggarty4,5, Yanhua Ren1, Srihari C. Sampath6, Yasmin L. Hurd1, Paul Greengard7, Alexander Tarakhovsky6, Anne Schaefer7, and Eric J. Nestler1,*

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.


Figure 1
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  		Fig. 1. Repeated cocaine administration represses G9a expression in the NAc through a {triangleup}FosB-dependent mechanism. (A) mRNA expression of H3K9/K27 KMTs and KDMs in the NAc 24 hours after repeated cocaine. (B) H3K9me2 levels in NAc 24 hours after repeated cocaine. (C) Analysis of gene expression after acute or repeated cocaine. Heat maps (*) show genes up-regulated in NAc 1 hour after a cocaine challenge in naïve animals (acute), in animals treated repeatedly with cocaine (repeated + acute), or in animals after 168 hours of withdrawal from repeated cocaine (repeated wd + acute). Associated heat maps show how genes were affected under the other two conditions. Desensitized transcriptional responses after repeated cocaine are indicated (***). (D) H3K9me2 levels in the NAc from NSE-tTA x tetOP-{triangleup}FosB mice on ({triangleup}FosB off) or off ({triangleup}FosB on) doxycycline 1 hour after repeated cocaine. (E) G9a mRNA expression in the NAc from NSE-tTA x tetOP-{triangleup}FosB mice on ({triangleup}FosB off) and off ({triangleup}FosB on) doxycycline and from mice infected with AAV-GFP or AAV-{triangleup}FosB. Data are presented as mean ± SEM. For statistical analyses, see the full figure legends in the supporting online text.

 

Figure 2
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  		Fig. 2. G9a in NAc regulates cocaine-induced behavioral plasticity. (A) Representative image of HSV-mediated transgene expression in the NAc. The cartoon of the coronal brain slice was taken from the mouse brain atlas. (B) Conditioned place preference for cocaine and (C) H3K9me2 levels in the NAc in animals infected with HSV-GFP, HSV-G9a, or HSV-G9aH1093K. (D) Conditioned place preference for cocaine and (E) H3K9me2 levels in the NAc in G9afl/fl animals infected with AAV-GFP or AAV-Cre. (F) Conditioned place preference for cocaine and (G) H3K9me2 levels in the NAc in animals receiving intra-NAc vehicle or BIX01294. Data are presented as mean ± SEM.

 

Figure 3
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  		Fig. 3. G9a in the NAc regulates cocaine-induced dendritic spine plasticity. (A) Quantitative G9a ChIP in the NAc from animals treated acutely or repeatedly with cocaine, at 1 or 24 hours, respectively. Adenine phosphoribosyltransferase (APRT) was used as a negative control. Data are presented as the relative fold difference from saline controls. (B) Quantitative H3K9me2 ChIP in the NAc from repeated cocaine–treated animals at 24 hours, presented as the relative fold difference from saline controls. (C) Dendritic spine analysis of animals infected with HSV-GFP, HSV-G9a, or HSV-{Delta}JunD after repeated cocaine, and dendritic spines in G9afl/fl mice after HSV-Cre infection. (D) Quantitative G9a ChIP in the NAc from NSE-tTA x tetOP-{triangleup}FosB mice on ({triangleup}FosB off) and off ({triangleup}FosB on) doxycycline. (E) Dendritic spine analysis in animals infected with AAV-GFP or AAV-{triangleup}FosB after repeated cocaine. Data are presented as mean ± SEM.

 

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