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

SUBMITTER: Wang DS

PROVIDER: S-EPMC4391624 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Memory deficits induced by inflammation are regulated by α5-subunit-containing GABAA receptors.

Wang Dian-Shi DS Zurek Agnieszka A AA Lecker Irene I Yu Jieying J Abramian Armen M AM Avramescu Sinziana S Davies Paul A PA Moss Stephen J SJ Lu Wei-Yang WY Orser Beverley A BA

Cell reports 20120920 3

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 ...[more]

PMID: 22999935

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Project description:BackgroundAlcohol's ability to potentiate the activity of γ-aminobutyric acid (GABA) at GABAA receptors has been implicated as a key mechanism underlying the behavioral effects of alcohol. The complex molecular biology of these receptors raises the possibility that particular receptor subtypes may play unique roles in alcohol's abuse-related effects and that subtype-selective ligands with therapeutic specificity against alcohol might be developed. This study evaluated the capacity of α5GABAA receptor ligands to alter selectively the reinforcing effects of alcohol.MethodsTwo groups of rhesus monkeys were trained to orally self-administer alcohol or sucrose under fixed-ratio schedules and limited daily access conditions. In addition, following daily self-administration sessions, the behavior of each monkey was scored for both species-typical and drug-induced behaviors.ResultsConcentrations of 1 to 6% alcohol maintained self-administration above water levels, engendered pharmacologically relevant blood alcohol levels ranging from 90 to 160 mg/dl, and produced changes in behavior typical of alcohol intoxication. Concentrations of 0.3 to 3% sucrose also reliably maintained self-administration. The α5GABAA receptor agonist QH-ii-066 enhanced and the α5GABAA receptor inverse agonist L-655,708 inhibited alcohol, but not sucrose drinking. The changes in alcohol drinking could be reversed with the α5GABAA receptor antagonist XLi-093. However, L-655,708 increased yawning in both alcohol and sucrose drinkers, possibly indicative of an anxiogenic effect.ConclusionsThese findings suggest a prominent and specific role for α5GABAA receptor mechanisms in the reinforcing effects of alcohol. Moreover, these results suggest that α5GABAA receptors may represent a novel pharmacological target for the development of medications to reduce drinking. Of ligands modulating this receptor, α5GABAA receptor inverse agonists may hold the most promise as alcohol pharmacotherapies.

Dataset Information

Memory deficits induced by inflammation are regulated by ?5-subunit-containing GABAA receptors.

Publications

Memory deficits induced by inflammation are regulated by α5-subunit-containing GABAA receptors.

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