Role of MyD88 in IL-1β and Ethanol Modulation of GABAergic Transmission in the Central Amygdala.

Michal Bajo,Yuri A Blednov,Tony D Davis,Florence P Varodayan,Marisa Roberto,David M Hedges,Reesha R Patel,Roman Vlkolinsky,Michael D Burkart

doi:10.3390/brainsci9120361

Abstract

Myeloid differentiation primary response protein (MyD88) is a critical neuroimmune adaptor protein in TLR (Toll-like receptor) and IL-1R (Interleukin-1 receptor) signaling complexes. These two pro-inflammatory families play an important role in the neurobiology of alcohol use disorder, specifically MyD88 regulates ethanol drinking, ethanol-induced sedation, and ethanol-induced deficits in motor coordination. In this study, we examined the role of MyD88 in mediating the effects of IL-1β and ethanol on GABAergic transmission in the central amygdala (CeA) of male mice using whole-cell patch-clamp recordings in combination with pharmacological (AS-1, a mimetic that prevents MyD88 recruitment by IL-1R) and genetic (Myd88 knockout mice) approaches. We demonstrate through both approaches that IL-1β and ethanol’s modulatory effects at CeA GABA synapses are not dependent on MyD88. Myd88 knockout potentiated IL-1β’s actions in reducing postsynaptic GABAA receptor function. Pharmacological inhibition of MyD88 modulates IL-1β’s action at CeA GABA synapses similar to Myd88 knockout mice. Additionally, ethanol-induced CeA GABA release was greater in Myd88 knockout mice compared to wildtype controls. Thus, MyD88 is not essential to IL-1β or ethanol regulation of CeA GABA synapses but plays a role in modulating the magnitude of their effects, which may be a potential mechanism by which it regulates ethanol-related behaviors.

Highlights

Acute and chronic ethanol exposure induce an innate immune response in the central nervous system (CNS) of humans, and this effect is replicated in preclinical models of alcohol use disorder (AUD) [1,2,3,4]
central amygdala (CeA) GABAergic transmission plays a critical role in mediating ethanol and anxiety-like behaviors [32], and we have previously identified modulatory roles for several innate immune elements [including LPS, IL-1β, the IL-1R1 ligand, and IL-1ra] at mouse CeA GABAergic synapses
We examined the role of MyD88 in mediating the effects of IL-1β and ethanol on GABAergic transmission in the central amygdala

Summary

Introduction

Acute and chronic ethanol exposure induce an innate immune response in the central nervous system (CNS) of humans, and this effect is replicated in preclinical models of alcohol use disorder (AUD) [1,2,3,4]. Manipulation of the innate immune system leads to alterations of the ethanol-related behaviors in rodents. This growing literature on innate immune responses critically contributing to the neurobiology of AUD [21,22,23] suggests that these pathways have high potential as targets for the development of new AUD therapeutic strategies [16,24,25,26].

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Results

Conclusion