Cocaine-mediated downregulation of microglial miR-124 expression involves promoter DNA methylation. Issue 11 (1st November 2016)

• Record Type: Journal Article
• Authors: Guo, Ming-Lei; Periyasamy, Palsamy; Liao, Ke; Kook, Yeon Hee; Niu, Fang; Callen, Shannon E.; Buch, Shilpa
• Is Part Of: Epigenetics. Volume 11:Issue 11(2016)
• Page Start: 819
• Page End: 830
• Publication Date: 2016-11-01
• Subjects: Cocaine -- microglial cells -- miR-124 -- neuroinflammation -- promoter DNA methylation; Epigenesis -- Periodicals; Epigenetica; 572.86505
• DOI: 10.1080/15592294.2016.1232233
• Languages: English
• ISSNs: 1559-2294

Abstract

ABSTRACT: Neuroinflammation plays a critical role in the development of reward-related behavior in cocaine self-administration rodents. Cocaine, one of most commonly abused drugs, has been shown to activate microglia both in vitro and in vivo . Detailed molecular mechanisms underlying cocaine-mediated microglial activation remain poorly understood. microRNAs (miRs) belonging to a class of small noncoding RNA superfamily have been shown to modulate the activation status of microglia. miR-124, one of the microglia-enriched miRs, functions as an anti-inflammatory regulator that maintains microglia in a quiescent state. To date, the possible effects of cocaine on microglial miR-124 levels and the associated underlying mechanisms have not been explored. In the current study, we demonstrated that cocaine exposure decreased miR-124 levels in both BV-2 cells and rat primary microglia. These findings were further validated in vivo, wherein we demonstrated decreased abundance of miR-124 in purified microglia isolated from cocaine-administered mice brains compared with cells from saline administered animals. Molecular mechanisms underlying these effects involved cocaine-mediated increased mRNA and protein expression of DNMTs in microglia. Consistently, cocaine substantially increased promoter DNA methylation levels of miR-124 precursors (pri-miR-124-1 and −2), but not that of pri-miR-124-3, both in vitro and in vivo . In summary, our findings demonstrated that cocaine exposure increased DNA methylation of miR-124 promoter resulting into its downregulation, which, in turn, led to microglial activation. Our results thus implicate that epigenetic modulation of miR-124 could be considered as a potential therapeutic approach to ameliorate microglial activation and, possibly, the development of cocaine addiction.