Abstract: The unbalance between synaptic （GluN2A，mediating the protective pathway）and extrasynaptic NMDA receptors（ NMDARs）（ GluN2B，mediating the excitotoxic pathway） has been found in Alzheimer’s disease （AD），indicating restoring the balance of GluN2A and GluN2B should be beneficial for AD. In this study，the GluN2B-selective antagonist，ifenprodil，and the non-selective NMDAR agonist，NMDA，had little effects on amyloid-beta （Abeta）-induced longterm potentiation （LTP） deficits. Enhancing the activity of GluN2A had a protective effect against Abeta，and specific activation of GluN2A and inhibition of GluN2B showed a better protective effect. The combination of ifenprodil and D-cycloserine （a co-activator of NMDRs similar to D-serine） led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone，meanwhile，the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity，suggesting that modulation of the balance between GluN2A and
GluN2B might be a good strategy for AD therapy.