Essential role of the histone methyltransferase G9a in cocaine-induced plasticity.
Journal:
Science 2010 JanAuthors:
Maze I, Covington HE, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Mouzon E, Neve RL, Haggarty SJ, Ren Y, Sampath SC, Hurd YL, Greengard P, Tarakhovsky A, Schaefer A, Nestler EJ
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
...[more] 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.[less]
Mesh Headings:
Animals, Behavior, Animal, Cocaine, Cocaine-Related Disorders, Dendritic Spines, Down-Regulation, Enzyme Repression, Gene Expression Profiling, Gene Expression Regulation, Histone-Lysine N-Methyltransferase, Histones, Lysine, Male, Methylation, Mice, Mice, Inbred C57BL, Neuronal Plasticity, Neurons, Nucleus Accumbens, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins c-fos, Reward, Self Administration, Transcription, Genetic