title: NMDA reduces Tau phosphorylation in rat hippocampal slices by targeting NR2A receptors, GSK3β, and PKC activities.
abstract: 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.
authors.affiliation: Groupe de Recherche en Neuroscience, Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7.
authors.forename: Audrée
authors.initials: A
authors.lastname: De Montigny
authors.affiliation: Groupe de Recherche en Neuroscience, Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7.
authors.forename: Ismaël
authors.initials: I
authors.lastname: Elhiri
authors.affiliation: Groupe de Recherche en Neuroscience, Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7.
authors.forename: Julie
authors.initials: J
authors.lastname: Allyson
authors.affiliation: Groupe de Recherche en Neuroscience, Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7.
authors.forename: Michel
authors.initials: M
authors.lastname: Cyr
authors.affiliation: Groupe de Recherche en Neuroscience, Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7.
authors.forename: Guy
authors.initials: G
authors.lastname: Massicotte
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D000939:Epitopes / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D002118:Calcium; D002867:Chromones; D000939:Epitopes; D018690:Excitatory Amino Acid Agonists; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D009025:Morpholines; D016202:N-Methylaspartate; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000605508:Gsk3b protein, rat