Chronic ethanol induces a pro-inflammatory switch in interleukin-1? regulation of GABAergic signaling in the medial prefrontal cortex of male mice

Neuroimmune pathways regulate brain function to influence complex behavior and play a role in several neuropsychiatric diseases, including alcohol use disorder (AUD). In particular, the interleukin-1 (IL-1) system has emerged as a key regulator of the brain's response to ethanol (alcohol). Here we investigated the mechanisms underlying ethanol-induced neuroadaptation of IL-1 beta signaling at GABAergic synapses in the prelimbic region of the medial prefrontal cortex (mPFC), an area responsible for integrating contextual information to mediate conflicting motivational drives. We exposed C57BL/6J male mice to the chronic intermittent ethanol vapor-2 bottle choice paradigm (CIE-2BC) to induce ethanol dependence, and conducted ex vivo electrophysiology and molecular analyses. We found that the IL-1 system regulates basal mPFC function through its actions at inhibitory synapses on prelimbic layer 2/3 pyramidal neurons. IL-1 beta can selectively recruit either neuroprotective (PI3K/ Akt) or pro-inflammatory (MyD88/p38 MAPK) mechanisms to produce opposing synaptic effects. In ethanol naive conditions, there was a strong PI3K/Akt bias leading to a disinhibition of pyramidal neurons. Ethanol dependence produced opposite IL-1 effects -enhanced local inhibition via a switch in IL-1 beta signaling to the canonical pro-inflammatory MyD88 pathway. Ethanol dependence also increased cellular IL-1 beta in the mPFC, while decreasing expression of downstream effectors (Akt, p38 MAPK). Thus, IL-1 beta may represent a key neural substrate in ethanol-induced cortical dysfunction. As the IL-1 receptor antagonist (kineret) is already FDA -approved for other diseases, this work underscores the high therapeutic potential of IL-1 signaling/neuro-immune-based treatments for AUD.