GABA_A receptor subtypes regulate stress-induced colon inflammation in Mice

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. Gamma-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 either early-life stress (ELS) 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 CD163 and TNF 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 labelled dextran orally and systemic absorption was measured. We also performed studies of mice with disruption of the GABAAR subunit alpha 3 gene (Gabra3–/– mice).

Results: Mice exposed to ELS had significantly altered GABAAR-mediated colonic contractility, impaired barrier function, and their colon tissue had increased levels of Gabra3 mRNA, compared to 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, demonstrating a pro-inflammatory 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 pharmacological activation of α3-GABAARs recapitulated colonic inflammation, whilst α1/4/5-GABAAR ligands were anti-inflammatory. These proteins might serve as therapeutic targets for treatment of colon inflammation or inflammatory bowel diseases.