title: Memory deficits induced by inflammation are regulated by α5-subunit-containing GABAA receptors.
abstract: 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 α5-subunit-containing γ-aminobutyric acid type A (α5GABA(A)) 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 α5GABA(A) receptor function. A tonic inhibitory current generated by α5GABA(A) 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 α5GABA(A) receptors in the hippocampus. Collectively, these results show that α5GABA(A) receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dian-Shi
authors.initials: DS
authors.lastname: Wang
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Zurek
authors.forename: Irene
authors.initials: I
authors.lastname: Lecker
authors.forename: Jieying
authors.initials: J
authors.lastname: Yu
authors.forename: Armen M
authors.initials: AM
authors.lastname: Abramian
authors.forename: Sinziana
authors.initials: S
authors.lastname: Avramescu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Davies
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Lu
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007858:Learning; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C496250:Gabra5 protein, mouse; D053583:Interleukin-1beta; D011963:Receptors, GABA-A