Article ; Online: Chronic ethanol induces a pro-inflammatory switch in interleukin-1β regulation of GABAergic signaling in the medial prefrontal cortex of male mice.
2023 Volume 110, Page(s) 125–139
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Mice ; Male ; Animals ; Ethanol/pharmacology ; Interleukin-1beta/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Myeloid Differentiation Factor 88/metabolism ; Mice, Inbred C57BL ; Alcoholism ; Prefrontal Cortex/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism |
| Chemical Substances | Ethanol (3K9958V90M) ; Interleukin-1beta ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Myeloid Differentiation Factor 88 ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) |
| Language | English |
| Publishing date | 2023-02-28 |
| Publishing country | Netherlands |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 639219-2 |
| ISSN | 1090-2139 ; 0889-1591 |
| ISSN (online) | 1090-2139 |
| ISSN | 0889-1591 |
| DOI | 10.1016/j.bbi.2023.02.020 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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