Microglia control escalation of drinking in alcohol dependent mice: Genomic and synaptic drivers

Abstract Background Microglia, the primary immune cells of the brain, are implicated in alcohol use disorder (AUD). However, it is not known if microglial activation contributes to the transition from alcohol use to AUD or is a consequence of alcohol intake. Methods We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex (mPFC) and CeA from the same animals used for behavioral studies. Results PLX5622 prevented escalations in voluntary alcohol intake and decreased anxiety-like behavior associated with alcohol dependence. PLX5622 also reversed expression changes in inflammatory-related genes and glutamatergic and GABAergic genes in the mPFC and CeA. At the cellular level in these animals, microglia depletion reduced inhibitory GABAA and excitatory glutamate receptor-mediated synaptic transmission in the CeA, supporting the hypothesis that microglia regulate dependence-induced changes in neuronal function. Conclusions Our multifaceted approach is the first to link microglia to the molecular, cellular and behavioral changes associated with the development of alcohol dependence, suggesting that microglia may also be critical for the development and progression of AUD.