%0 Journal Article
%T NMDA Reduces Tau Phosphorylation in Rat Hippocampal Slices by Targeting NR2A Receptors, GSK3¦Â, and PKC Activities
%A Audr¨¦e De Montigny
%A Isma£¿l Elhiri
%A Julie Allyson
%A Michel Cyr
%A Guy Massicotte
%J Neural Plasticity
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/261593
%X The molecular mechanisms that regulate Tau phosphorylation are complex and currently incompletely understood. In the present study, pharmacological inhibitors were deployed to investigate potential processes by which the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors modulates Tau phosphorylation in rat hippocampal slices. Our results demonstrated that Tau phosphorylation at Ser199-202 residues was decreased in NMDA-treated hippocampal slices, an effect that was not reproduced at Ser262 and Ser404 epitopes. NMDA-induced reduction of Tau phosphorylation at Ser199-202 was further promoted when NR2A-containing receptors were pharmacologically isolated and were completely abrogated by the NR2A receptor antagonist NVP-AAM077. Compared with nontreated slices, we observed that NMDA receptor activation was reflected in high Ser9 and low Tyr216 phosphorylation of glycogen synthase kinase-3 beta (GSK3¦Â), suggesting that NMDA receptor activation might diminish Tau phosphorylation via a pathway involving GSK3¦Â inhibition. Accordingly, we found that GSK3¦Â inactivation by a protein kinase C- (PKC-) dependent mechanism is involved in the NMDA-induced reduction of Tau phosphorylation at Ser199-202 epitopes. Taken together, these data indicate that NR2A receptor activation may be important in limiting Tau phosphorylation by a PKC/GSK3¦Â pathway and strengthen the idea that these receptors might act as an important molecular device counteracting neuronal cell death mechanisms in various pathological conditions. 1. Introduction Over the years, a growing number of reports have revealed that, in contrast to the destructive effects of excessive N-methyl-D-aspartate (NMDA) receptor activity, synaptic NMDA receptor stimulation under physiological conditions could result in the activation of prosurvival mechanisms in neurons [1¨C5]. For instance, it appears that tonic activation of NMDA receptors in hippocampal neurons is required for maintaining synaptic stability, through a mechanism involving modulation of dendritic protein synthesis [6]. In fact, it has been proposed that the tonic activity of NMDA receptors is a crucial mechanism regulating calcium mobilization in neurons, as NMDA receptor deprivation rapidly increases the synaptic expression of surface GluR1 subunits and the incorporation of toxic Ca2+-permeable ¦Á-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors at glutamatergic synapses [7, 8]. Fiumelli et al. [9] demonstrated that suppression of NMDA receptor activity by global antagonists (MK801 or AP5) can interfere with both phosphorylation
%U http://www.hindawi.com/journals/np/2013/261593/