Memory Deficits Induced by Inflammation Are Regulated by α5-Subunit-Containing GABAA Receptors

SummarySystemic inflammation causes learning and memory deficits through mechanisms that remain poorly understood. Here, we studied the pathogenesis of memory loss associated with inflammation and found that we could reverse memory deficits by pharmacologically inhibiting α5-subunit-containing γ-aminobutyric acid type A (α5GABAA) receptors and deleting the gene associated with the α5 subunit. Acute inflammation reduces long-term potentiation, a synaptic correlate of memory, in hippocampal slices from wild-type mice, and this reduction was reversed by inhibition of α5GABAA receptor function. A tonic inhibitory current generated by α5GABAA receptors in hippocampal neurons was increased by the key proinflammatory cytokine interleukin-1β through a p38 mitogen-activated protein kinase signaling pathway. Interleukin-1β also increased the surface expression of α5GABAA receptors in the hippocampus. Collectively, these results show that α5GABAA receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► Inflammation-induced contextual fear memory loss depends on α5GABAA receptors
► Inflammation-induced impairment of LTP depends on α5GABAA receptors
► IL-1β enhances the tonic current mediated by α5GABAA receptors in hippocampal neurons
► IL-1β increases the surface expression of α5GABAA receptors in the hippocampus