Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Dr. Wei-Yang Lu

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.

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