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Type: Journal article
Title: MK-801 impairs working memory on the Trial-Unique Nonmatch-to-Location test in mice, but this is not exclusively mediated by NMDA receptors on PV+ interneurons or forebrain pyramidal cells
Author: Sokolenko, E.
Nithianantharajah, J.
Jones, N.C.
Citation: Neuropharmacology, 2020; 171
Publisher: Elsevier
Issue Date: 2020
ISSN: 0028-3908
Statement of
Elysia Sokolenko, Jess Nithianantharajah, Nigel C. Jones
Abstract: NMDA receptors are widely expressed throughout the brain on many cell types, and loss of function of these receptors (ie: NMDAr hypofunction) is a candidate mechanism explaining working memory impairment in schizophrenia. However, the cellular source driving the working memory deficits caused by NMDA hypofunction has not been explored. The aim of this study was to assess the contribution of NMDAr on pyramidal cells and parvalbumin (PV+) interneurons to impairments in working memory induced by NMDAr hypofunction. We excised GluN1 - the gene encoding the obligatory subunit of the NMDAr from PV + interneurons or CaMKII + pyramidal cells - using Cre-lox technology. Adult male PV GluN1 KO (n = 10) and CaMKIIα GluN1 KO mice (n = 9) and WT controls (n = 10 and n = 13) were trained to perform the Trial-Unique Nonmatching-to-Location (TUNL) task of working memory. Once trained, mice received the NMDA receptor antagonist MK-801 (0.1 and 0.3 mg/kg ip), and working memory assessed. Neither task acquisition nor working memory differed between the two transgenic lines and WT littermates. MK-801 dose-dependently decreased working memory accuracy in all strains (p < 0.001). PV GluN1 KO mice were sensitised to the impairing effects of MK-801 (p = 0.04), whereas CaMKIIα GluN1 KO mice showed equivalent working memory deficits as WT. Developmental NMDAr hypofunction at either PV + interneurons or forebrain pyramidal cells is not sufficient to impair working memory, and neither of these cell types exclusively mediates working memory impairment caused by NMDA receptor antagonism. Reduced NMDAr signalling at PV + interneurons could predispose circuits to NMDAr hypofunction magnifying deficits in working memory.
Keywords: Working memory; NMDA receptor hypofunction; TUNL task; parvalbumin interneurons; CaMKII pyramidal cells
Rights: © 2020 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.neuropharm.2020.108103
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