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 (GSK3β), suggesting that NMDA receptor activation might diminish Tau phosphorylation via a pathway involving GSK3β inhibition. Accordingly, we found that GSK3β 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/GSK3β 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 [1–5]. 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 α-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
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