Event Abstract Back to Event Inflammation and memory deficits: a role for extrasynaptic GABAA receptors Dian-Shi Wang1* and Beverley Orser1, 2 1 University of Toronto, Departments of Physiology and Anesthesia, Canada 2 Sunny brook Health Sciences Centre, Canada γ-Aminobutyric acid type A receptors (GABAARs) are the main inhibitory receptors in the central nervous system. Two forms of GABAAR-mediated inhibition exist: phasic inhibition which is mediated by synaptic GABAARs clustered at postsynaptic terminals, and tonic inhibition which is generated by high-affinity, slowly desensitizing extrasynaptic GABAARs that are activated by low ambient concentrations of GABA. Cognitive deficits and memory impairment occur in a variety of inflammatory disorders in which proinflammatory cytokines such as IL-1β and TNF-α are produced in the brain. Proinflammatory cytokines have been shown to interfere with cognitive function. Here we test the hypothesis that the prototypic proinflammatory cytokine, IL-1β enhances the tonic conductance and thereby impair memory during brain inflammation. The effects of IL-1β on phasic GABAAR function were also tested. We also sought to determine the signaling pathways involved in IL-1&beta's effects. Whole-cell voltage clamp techniques were used to record tonic, synaptic and GABA-evoked currents in cultured murine hippocampal neurons. Pretreatment of neurons with IL-1β (20 ng/ml, ≈ 1.18 nM) for 20 min increased the tonic current density (≈ 44.3%, n = 22, P < 0.05) in comparison with that of vehicle control. Acute perfusion of IL-1β (20 ng/ml) for 2 min also caused an increase in the tonic current (36.2 ± 2.5%, mean ± SEM; n = 6, P < 0.05). In contrast, both the amplitude and frequency of mIPSCs were suppressed by IL-1β. IL-1β also inhibited currents activated by GABA at concentrations above 1 µM. In addition, IL-1 receptor antagonist can block both the enhancing effect on tonic conductance and the inhibitory effect on GABA evoked currents of IL-1β suggesting that type I IL-1 receptor mediates the effects of IL-1β. Furthermore, P38 MAPK inhibitor SB203580 (20 µM) could block the enhancing effect of IL-1β on tonic conductance, whereas the inhibitory effect of IL-1β on GABA-evoked currents could not be blocked by SB203580, but PI3k inhibitor LY294002 (20 µM) and Wortmanin (0.1 µM) could abolish the inhibitory effect of IL-1β. Our results show that IL-1β acts on type 1 IL-1 receptor to enhance the tonic conductance through P38 MAPK pathway, whereas to inhibit the synaptic conductance via PI3k pathway. The enhancing effect of IL-1β on tonic conductance may impair memory in inflammatory disorders. Future study will decipher the mechanisms underlying the signaling pathways that differentially modulate IL-1β on tonic and synaptic GABAAR function in hippocampal neurons and whether such changes influence memory behavior. Conference: B.R.A.I.N. platform in Physiology poster day 2009, Toronto, ON, Canada, 16 Dec - 16 Dec, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Wang D and Orser B (2009). Inflammation and memory deficits: a role for extrasynaptic GABAA receptors. Front. Neurosci. Conference Abstract: B.R.A.I.N. platform in Physiology poster day 2009. doi: 10.3389/conf.neuro.03.2009.17.047 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Dec 2009; Published Online: 18 Dec 2009. * Correspondence: Dian-Shi Wang, University of Toronto, Departments of Physiology and Anesthesia, Toronto, Canada, dianshi.wang@utoronto.ca Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Dian-Shi Wang Beverley Orser Google Dian-Shi Wang Beverley Orser Google Scholar Dian-Shi Wang Beverley Orser PubMed Dian-Shi Wang Beverley Orser Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.