The Role of α5GABA(A) Receptors in Brain Inflammation
Abstract
Microglia critically regulate brain inflammation. GABAA receptors that contain the α5-subunit (α5GABAA) exhibit high sensitivity to GABA and confer tonic activity. Moreover, α5GABAA receptors have been associated with brain inflammation. This study investigates the role of α5GABAA receptors in microglial activation. Immunohistochemistry revealed that in response to intraperitoneal lipopolysaccharide (LPS), α5-subunit null mice exhibited significantly higher expression of IL-1β in hippocampal microglia. Neuronal-glial co-cultures treated with α5GABAA receptor inverse agonist L655,708 drastically increased microglial IL-1β expression. Surprisingly, ELISA of media from L655,708-treated co-cultures revealed a considerably lower concentration of IL-1β. Treating cultured primary astrocytes with LPS increased IL-1β secretion, which was reduced by co-treatment with L655,708. Cultured primary microglia did not respond to LPS/L655,708. When grown in LPS-primed astrocytic conditioned media, primary microglia secreted IL-1β, which increased in the presence of L655,708. These data suggests that astrocytes express α5GABAA receptors, which regulate astrocytic activity and hence indirectly modulate microglial activation.