Cocaine-mediated activation of microglia and microglial MeCP2 and BDNF production

Abstract

The molecular substrates underlying cocaine reinforcement and addiction have been studied for decades, with a primary focus on signaling molecules involved in modulation of neuronal communication. Brain-derived neurotrophic factor (BDNF) is an important signaling molecule involved in neuronal dendrite and spine modulation. Methyl CpG binding protein 2 (MeCP2) binds to the promoter region of BDNF to negatively regulate its expression and cocaine can recruit MeCP2 to alter the expression of genes such as BDNF that are involved in synaptic plasticity. For several decades, BDNF has been implicated in mediating synaptic plasticity associated with cocaine abuse, and most studies report that neurons are the primary source for BDNF production in the brain. The current study assessed the effects of intravenous cocaine self-administration on microglial activation, and MeCP2 and BDNF expression in reward regions of the brain in vivo, as well as determined specific effects of cocaine exposure on MeCP2 and BDNF expression in human primary neurons and microglia. The results from this study highlight a distinct molecular pathway in microglia through which cocaine increases BDNF, including the phosphorylation of MeCP2 its subsequent translocation from the nucleus to the cytosol, which frees the BDNF promoter and permits its transcriptional activation. Results from these studies show for the first time that cocaine self-administration increases microglial activation, and that microglial MeCP2 is a sensitive target of cocaine resulting in increased release of BDNF from microglia, and possibly contributing to cocaine-induced synaptic plasticity.

Effects of Cocaine on Human Glial-Derived Extracellular Vesicles

“…These results are consistent with previous reports that dectin-1 and TLR2 activation modulate macrophage function in the central nervous system and reduce the damaging effects of inflammation ( Dennehy et al, 2008 ; Kelly et al, 2008 ; Lee et al, 2009 ; Gensel et al, 2015 ). Furthermore, these results support previous studies showing that cocaine activates brain microglial cells and that activated microglia-derived EVs play important roles in neuroinflammation and modulation of cell-to-cell communication ( Cotto et al, 2018 ; Periyasamy et al, 2018 ).…”

Changes in the Expression of DNA Methylation Related Genes in Leukocytes of Persons with Alcohol and Drug Dependence

“…A study reported increased levels of MeCP2 in dorsal striatal neurons in rats after cocaine administration [30]. Another study observed that cocaine administration increases MeCP2 expression in hippocampus, frontal cortex, and NAc of rats [31]. Deng et.…”

Image_4.JPEG

“…These results are consistent with previous reports that dectin-1 and TLR2 activation modulate macrophage function in the central nervous system and reduce the damaging effects of inflammation (Dennehy et al, 2008;Kelly et al, 2008;Lee et al, 2009;Gensel et al, 2015). Furthermore, these results support previous studies showing that cocaine activates brain microglial cells and that activated microgliaderived EVs play important roles in neuroinflammation and modulation of cell-to-cell communication (Cotto et al, 2018;Periyasamy et al, 2018).…”