High Mobility Group Box 1/Toll-like Receptor 4 Signaling Increases GABRB3 Expression in Alcohol Exposure

Introduction: Prefrontal cortex (PFC) and striatal neurotransmitter homeostasis is affected by alcohol dependence. In this study, the microarray dataset from the Gene Expression Omnibus (GEO) database were downloaded. The prefrontal and striatum data were cross analyzed to reveal the co-effects of alcohol dependence on the two brain regions of mice. Methods: The GSE123114 microarray profile was downloaded from the GEO database, and differentially expressed genes (DEGs) between the two groups were acquired by GEO2R. KEGG analyses were performed to identify the pivotal pathways of these DEGs. Key differential gene expressions and their mechanism associated with alcohol exposure were investigated by an intraperitoneal alcohol model. Results: A total of 13 overlapping DEGs from the PFC and striatal datasets of the GSE123114 microarray profile were identified, and they were significantly enriched in the morphine addiction pathway. The transcript levels and protein expression of Gabrb3 were consistent with the microarray data both in the PFC and striatum. The transcript levels of HMGB1, TLR4, TNF alpha and IL-10 were upregulated in the PFC and striatum of mice in the alcohol group. The HMGB1 inhibitor decreased Gabrb3 transcript and protein levels as well as TNF alpha and IL-10 transcript levels both in the PFC and striatum in the intraperitoneal alcohol model mice. Discussion: Through the reanalysis of GSE123114 microarray profile, we found that Gabrb3 is a key gene associated with alcohol exposure. In further experiments, our findings suggest that alcohol exposure modulates Gabrb3 expression through the HMGB1/TLR4 pathway. Moreover, inflammation-associated factors, such as IL-10 and TNF alpha, may be related to the HMGB1/TLR4-mediated regulation of GABRB3 expression in alcohol exposure.