Modulating the balance of synaptic and extrasynaptic NMDA receptors (NMDARs) shows priority over non‐selective NMDAR antagonists against beta‐amyloid induced neurotoxicity

Abstract

Alzheimer's disease (AD) patients suffer a disturbance in the balance between synaptic NMDARs (NR2A, mediating the protective pathway) and extrasynaptic NMDARs (NR2B, mediating the excitotoxic pathway), and restoring the balance of NR2A and NR2B should be beneficial for AD. Aβ treated hippocampal slices and Aβ icv injection animals were used as AD models in this study. Long‐term potentiation (LTP) and behavior test were used to evaluate the effects of drugs and signal pathways were analyzed by Western Blotting. Specific activation of NR2A and inhibition of NR2B showed the best protective effect against Aβ‐induced long‐term potentiation (LTP) deficits. In Aβ icv injection animals, the combination of ifenprodil and D‐cycloserine (a co‐activator of NMDRs similar to D‐serine) showed better protective effects against Aβ‐induced cognitive deficits (nest building, novel object recognition and Morris water maze) than ifenprodil or D‐cycloserine alone. The ratio of NR2A to NR2B, TORC dephosphorylation and ERK1/2 activation (which could be initiated by NR2A) decreased in the hippocampal tissues of Aβ‐treated animals. As a result, the activation of CREB and the content of brain‐derived BDNF decreased. The combination of ifenprodil and D‐cycloserine showed the best protective effects, indicating that Aβ‐induced toxicology was mediated both by inhibiting NR2A and enhancing NR2B. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed good effects against Aβ‐induced neurotoxicity, suggesting that modulation of the balance between NR2A and NR2B could be a potential strategy for AD drug development and therapy.Support or Funding InformationProject supported by the National Natural Science Foundation of China (81202505)