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

TLDR

Cocaine-induced changes in gene expression alter neuronal morphology and behavior, potentially underlying addiction. Repression of the histone methyltransferase G9a by the cocaine‑induced transcription factor ΔFosB reduces H3K9 dimethylation in the nucleus accumbens. Loss of G9a‑mediated H3K9 dimethylation increases dendritic spine plasticity and enhances cocaine preference, establishing its essential role in cocaine‑induced structural and behavioral plasticity.

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 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.