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

Systemic 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 alpha 5-subunit-containing gamma-aminobutyric acid type A (alpha 5GABA(A)) receptors and deleting the gene associated with the alpha 5 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 alpha 5GABA(A) receptor function. A tonic inhibitory current generated by alpha 5GABA(A) receptors in hippocampal neurons was increased by the key proinflammatory cytokine interleukin-1 beta through a p38 mitogen-activated protein kinase signaling pathway. Interleukin-1 beta also increased the surface expression of alpha 5GABA(A) receptors in the hippocampus. Collectively, these results show that alpha 5GABA(A) receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.