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Chronic ethanol induces a pro-inflammatory switch in interleukin-1β regulation of GABAergic signaling in the medial prefrontal cortex of male mice.
- Source :
-
Brain, Behavior & Immunity . May2023, Vol. 110, p125-139. 15p. - Publication Year :
- 2023
-
Abstract
- • IL-1β decreases GABA release via a neuroprotective pathway in naïve mice. • Ethanol dependence increases IL-1β. • Ethanol dependence causes a synaptic switch in IL-1β signaling. • IL-1β increases GABA release via a pro-inflammatory pathway in dependent 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-1β 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-1β can selectively recruit either neuroprotective (PI3K/Akt) or pro-inflammatory (MyD88/p38 MAPK) mechanisms to produce opposing synaptic effects. In ethanol naïve 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-1β signaling to the canonical pro-inflammatory MyD88 pathway. Ethanol dependence also increased cellular IL-1β in the mPFC, while decreasing expression of downstream effectors (Akt, p38 MAPK). Thus, IL-1β 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/neuroimmune-based treatments for AUD. [ABSTRACT FROM AUTHOR]
- Subjects :
- *SYNAPSES
*PREFRONTAL cortex
*ALCOHOLISM
*PYRAMIDAL neurons
*ETHANOL
*LABORATORY mice
Subjects
Details
- Language :
- English
- ISSN :
- 08891591
- Volume :
- 110
- Database :
- Academic Search Index
- Journal :
- Brain, Behavior & Immunity
- Publication Type :
- Academic Journal
- Accession number :
- 163046742
- Full Text :
- https://doi.org/10.1016/j.bbi.2023.02.020