Blockade of NR2A-Containing NMDA Receptors Induces Tau Phosphorylation in Rat Hippocampal Slices

Abstract

Physiological activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been proposed to play a key role in both neuronal cell function and dysfunction. In the present study, we used selective NMDA receptor antagonists to investigate the involvement of NR2A and NR2B subunits in the modulatory effect of basal NMDA receptor activity on the phosphorylation of Tau proteins. We observed, in acute hippocampal slice preparations, that blockade of NR2A-containing NMDA receptors by the NR2A antagonist NVP-AAM077 provoked the hyperphosphorylation of a residue located in the proline-rich domain of Tau (i.e., Ser199). This effect seemed to be Ser199 specific as there was no increase in phosphorylation at Ser262 and Ser409 residues located in the microtubule-binding and C-terminal domains of Tau proteins, respectively. From a mechanistic perspective, our study revealed that blockade of NR2A-containing receptors influences Tau phosphorylation probably by increasing calcium influx into neurons, which seems to rely on accumulation of new NR1/NR2B receptors in neuronal membranes and could involve the cyclin-dependent kinase 5 pathway.

Activity-Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers

“…Currently, only one study suggests an interaction between tau and myosin based on their colocalization within neurofibrillary tangles found in AD and FTD patients' brains . Moreover, myosin VI was shown to modulate tau-dependent neurodegeneration in the Thy-Tau22 Drosophila model (Blard et al, 2007). However, these studies provide no direct evidence for a physiological interaction between tau and myosin.…”

“…The difference in tau behavior depending on the stimulus driving it to the synapse is puzzling and may rely on the variation in the phosphorylation profile (Allyson et al, 2010;Mondragó nRodríguez et al, 2012). It is now well accepted that tau function and localization to the membrane, nucleus, synapse, or axons is modulated by phosphorylation (Mandell and Banker, 1996;Sultan et al, 2011;Pooler et al, 2012;Hoover et al, 2010).…”

Overactivation of NR2B‐containing NMDA receptors through entorhinal–hippocampal connection initiates accumulation of hyperphosphorylated tau in rat hippocampus after transient middle cerebral artery occlusion

“…This finding, together with the previous in vitro study demonstrating that an NR2A antagonist increases tau phosphorylation in hippocampal slices (Allyson et al . ), suggests that NR2A‐containing NMDAR activity plays an essential role in limiting tau phosphorylation under physiological conditions. Conversely, the increase in hyperphosphorylated tau in MCAO rats was prevented by inhibition of NR2B, but not NR2A activity.…”

Effects of NMDA receptor antagonists with different subtype selectivities on retinal spreading depression

“…To ensure that the selectivity of each drug for its respective preferring NMDA receptor subtype(s) was effective in our study with the chick retina, the concentration range to be tested was carefully selected on the basis of their NMDA receptor subunit selectivity reported in the literature (Table 1). NVP‐AAM077 is preferably selective for GluN2A subunit at concentrations less than 0.1 µmol·L −1 (Auberson et al ., 2002; Liu et al ., 2004; Allyson et al ., 2010), although lower potencies were reported by other studies (Feng et al ., 2004; Paoletti and Neyton, 2007). Accordingly, NVP‐AAM077 was tested at the following concentrations: 0.03, 0.1 and 0.3 µmol·L −1 .…”