GABAA Receptor Subtypes Regulate Stress-Induced Colon Inflammation in Mice

Abstract

Background & Aims: Psychological stress, in early life or adulthood, is a significant risk factor for inflammatory disorders, including inflammatory bowel diseases. However, little is known about the mechanisms by which emotional factors affect the immune system. γ-Aminobutyric acid type A receptors (GABAARs) regulate stress and inflammation, but it is not clear whether specific subtypes of GABAARs mediate stress-induced gastrointestinal inflammation. We investigated the roles of different GABAAR subtypes in mouse colon inflammation induced by 2 different forms of psychological stress. Methods: C57BL/6J mice were exposed to early-life stress, and adult mice were exposed to acute-restraint stress; control mice were not exposed to either form of stress. We collected colon tissues and measured contractility using isometric tension recordings; colon inflammation, based on levels of cluster of differentiation 163 and tumor necrosis factor messenger RNA (mRNA) and protein and myeloperoxidase activity; and permeability, based on levels of tight junction protein 1 and occludin mRNA and protein. Mice were given fluorescently labeled dextran orally and systemic absorption was measured. We also performed studies of mice with disruption of the GABAAR subunit α3 gene (Gabra3–/– mice). Results: Mice exposed to early-life stress had significantly altered GABAAR-mediated colonic contractility and impaired barrier function, and their colon tissue had increased levels of Gabra3 mRNA compared with control mice. Restraint stress led to colon inflammation in C57/BL6J mice but not Gabra3–/– mice. Colonic inflammation was induced in vitro by an α3-GABAAR agonist, showing a proinflammatory role for this receptor subtype. In contrast, α1/4/5-GABAAR ligands decreased the expression of colonic inflammatory markers. Conclusions: We found stress to increase expression of Gabra3 and induce inflammation in mouse colon, together with impaired barrier function. The in vitro pharmacologic activation of α3-GABAARs recapitulated colonic inflammation, whereas α1/4/5-GABAAR ligands were anti-inflammatory. These proteins might serve as therapeutic targets for treatment of colon inflammation or inflammatory bowel diseases.