Essential role of the histone methyltransferase G9a in cocaine-induced plasticity.
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 DeltaFosB. 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.
Maze
Ian
I
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
Covington
Herbert E
HE
Dietz
David M
DM
LaPlant
Quincey
Q
Renthal
William
W
Russo
Scott J
SJ
Mechanic
Max
M
Mouzon
Ezekiell
E
Neve
Rachael L
RL
Haggarty
Stephen J
SJ
Ren
Yanhua
Y
Sampath
Srihari C
SC
Hurd
Yasmin L
YL
Greengard
Paul
P
Tarakhovsky
Alexander
A
Schaefer
Anne
A
Nestler
Eric J
EJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000209:etiology / Q000378:metabolism; D049229:Dendritic Spines / Q000502:physiology; D015536:Down-Regulation; D004794:Enzyme Repression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012201:Reward; D012646:Self Administration; D014158:Transcription, Genetic
C483819:Fosb protein, mouse; D006657:Histones; D016760:Proto-Oncogene Proteins c-fos; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D003042:Cocaine; D008239:Lysine