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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.

Pubmed ID: 20056891

Authors

  • 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

Journal

Science (New York, N.Y.)

Publication Data

January 8, 2010

Associated Grants

  • Agency: NIDA NIH HHS, Id: P01 DA008227
  • Agency: NIDA NIH HHS, Id: P01 DA008227-120001
  • Agency: NIDA NIH HHS, Id: P01 DA008227-129001
  • Agency: NIDA NIH HHS, Id: P01 DA008227-13
  • Agency: NIDA NIH HHS, Id: P01 DA008227-14
  • Agency: NIDA NIH HHS, Id: P01 DA008227-15
  • Agency: NIDA NIH HHS, Id: P01 DA008227-16
  • Agency: NIDA NIH HHS, Id: P01 DA008227-170003
  • Agency: NIDA NIH HHS, Id: P01 DA008227-180003
  • Agency: NIDA NIH HHS, Id: P01 DA010044
  • Agency: NIDA NIH HHS, Id: P01 DA010044-14
  • Agency: NIDA NIH HHS, Id: P01 DA010044-140005
  • Agency: NIDA NIH HHS, Id: P01 DA010044-149002
  • Agency: NIDA NIH HHS, Id: P01 DA010044-14S1
  • Agency: NIDA NIH HHS, Id: P01 DA010044-14S10005
  • Agency: NIDA NIH HHS, Id: P01 DA010044-14S19002
  • Agency: NIDA NIH HHS, Id: P01 DA010044-15
  • Agency: NIDA NIH HHS, Id: P01 DA010044-150005
  • Agency: NIDA NIH HHS, Id: P01 DA010044-159002
  • Agency: NIDA NIH HHS, Id: P01 DA08227
  • Agency: PHS HHS, Id: P0110044
  • Agency: NIDA NIH HHS, Id: R01 DA007359
  • Agency: NIDA NIH HHS, Id: R01 DA007359-02
  • Agency: NIDA NIH HHS, Id: R01 DA007359-17
  • Agency: NIDA NIH HHS, Id: R01 DA007359-18
  • Agency: NIDA NIH HHS, Id: R01 DA007359-19
  • Agency: NIDA NIH HHS, Id: R01 DA007359-20
  • Agency: NIDA NIH HHS, Id: R01 DA007359-21
  • Agency: NIDA NIH HHS, Id: R01 DA007359-22
  • Agency: NIDA NIH HHS, Id: R01 DA014133
  • Agency: NIDA NIH HHS, Id: R01 DA07359

Mesh Terms

  • 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