Effect of ethanol-dependence and withdrawal in the modulatory action of proinflammatory cytokine IL-6 on synaptic transmission and neuronal functions in the amygdala

Abstract

The implications of the neuroimmune system in the pathogenesis of alcohol use disorders (AUD) have been undeniable. Cytokines have the function of stimulating cellular immune response and play a fundamental role in the control and modulation of local and systemic inflammatory responses, causing a constant balance between proinflammatory and anti-inflammatory cytokines. In this regard, Prof. Marisa Roberto research group showed that the anti-inflammatory IL-10 cytokine in the amygdala serves as a regulator of GABA transmission, drinking and anxiety-like behaviors. Notably, microglia, the brain's primary innate immune cells, are essential in escalation of voluntary ethanol intake, anxiety-like behaviors associated with ethanol dependence, and dependence-induced changes in amygdala neuronal function. Moreover, prefrontal cortex and amygdala transcriptome analysis revealed that microglia depletion downregulates inflammatory- and synaptic- (GABA and glutamate) related genes including those for the Interleukin-6 (IL-6) system. IL-6 is a multifunctional cytokine with a mainly pro-inflammatory profile but has also anti-inflammatory properties. In the brain IL-6 is produced by both glial cells and neurons. Growing evidences have shown increases in mRNA expression of the brain Il6ra (gene encoding IL-6 receptor; IL-6R) with drinking in mice and alcohol-preferring rats. Notably, Il6 null mutant mice display reduced ethanol intake and transgenic mice overexpressing IL-6 in astrocytes show impaired stress-coping behavior versus non-transgenic littermates. Thus, IL-6 represents an attractive candidate to test the hypothesis that cytokines are integral to the synaptic neuroadaptations occurring in GABAergic signaling in the amygdala that contribute to the escalation of drinking and the associated negative affect. Considering these evidences, we will use both male and female mice in our behavioral, molecular, and electrophysiological studies to explore potential sex-differences in the IL-6-dependent responses to excessive drinking. The aims of our study are: i) evaluate the effect of ethanol dependence and withdrawal in the Il6ra expression in amygdala neurons, astrocytes and microglia; and ii) investigate the effect of ethanol-dependence and withdrawal in the modulatory action of IL-6 on synaptic transmission and neuronal functions in the amygdala. Understanding these sex-differences is key for developing effective sex-appropriate therapeutic strategies targeting IL-6 for the treatment of AUD particularly for the withdrawal/negative affective state. (AU)