Dysregulation of synaptic and extrasynaptic N-methyl-D-aspartate receptors induced by amyloid-β

The toxicity of amyloid-beta（Aβ） is strongly associated with Alzheimer’s disease（AD）,which has a high incidence in the elderly worldwide.Recent evidence showed that alteration in the activity of N-methyl-D-aspartate receptors（NMDARs） plays a key role in Aβ-induced neurotoxicity.However,the activation of synaptic and extrasynaptic NMDARs has distinct consequences for plasticity,gene regulation,neuronal death,and Aβ production.This review focuses on the dysregulation of synaptic and extrasynaptic NMDARs induced by Aβ.On one hand,Aβ downregulates the synaptic NMDAR response by promoting NMDAR endocytosis,leading to either neurotoxicity or neuroprotection.On the other hand,Aβ enhances the activation of extrasynaptic NMDARs by decreasing neuronal glutamate uptake and inducing glutamate spillover,subsequently causing neurotoxicity.In addition,selective enhancement of synaptic activity by low doses of NMDA,or reduction of extrasynaptic activity by memantine,a non-competitive NMDAR antagonist,halts Aβ-induced neurotoxicity.Therefore,future neuroprotective drugs for AD should aim at both the enhancement of synaptic activity and the disruption of extrasynaptic NMDAR-dependent death signaling.

Synaptic non-GluN2B-containing NMDA receptors regulate tyrosine phosphorylation of GluN2B 1472 tyrosine site in rat brain slices

Activation of N-methyl-D-aspartate receptors（NMDARs）mediates changes in the phosphorylation status of the glutamate receptors themselves.Previous studies have indicated that during synaptic activity,tyrosine kinases（Src and Fyn）or phosphatases（PTPαand STEP）are involved in regulating the phosphorylation of NMDARs.In this study,we used immunoblotting to investigate the role of an NMDAR subpopulation on the phosphorylation level of the GluN2B subunit at the Y1336 and Y1472sites in rat brain slices after NMDA treatment.We found that NMDA stimulation dramatically decreased the phosphorylation level of GluN2B at Y1472 in a dose-and time-dependent manner,but not at Y1336.Extrasynaptic NMDAR activation did not reduce the phosphorylation of GluN2B at Y1472.In addition,ifenprodil,a selective antagonist of GluN2Bcontaining NMDARs,did not abolish the decreased phosphorylation of GluN2B at Y1472 triggered by NMDA.These results suggest that the activation of synaptic GluN2A-containing NMDARs is required for the decreased phosphorylation of GluN2B at Y1472that is induced by NMDA treatment in rat brain slices.