Objective N-methyl-D-aspartate receptors (NMDARs) play an important role in learning and memory.NR2A and NR2B subunits are predominant in the prefrontal cortex.Although growing evidence implicates that specific subunit-containing NMDARs correlate with subsequent modifications of synaptic plasticity, whether the up-regulation of NR2A subunit influences prefrontal synaptic plasticity and prefrontal cortex-related memory is not yet clear.Methods In the present study, we combined electrophysiological technique and behavioral method to investigate effects of NR2A overexpression on prefrontal synaptic plasticity and prefrontal cortex-related memory.Results (1) Western blotting results showed that the level of NR2A, but not NR2B protein, was significantly higher in prefrontal cortex of the transgenic mice than wild type mice.(2) Whole cell Patch-clamp recording showed that the ratio of NR2A/NR2B current increased significantly in transgenic mice compared with that in wide type mice; the decay time of evoked NMDAR-EPSC was sharply faster in transgenic mice than in wide type mice.However, the rise time of evoked NMDAR-EPSC in transgenic mice did not differ significantly from wide type mice.(3) Field potential recording showed that no significant differences were measured in basal synaptic transmission between transgenic mice and wide type mice; however, both prefrontal long-term potentiation (LTP) and long-term depression (LTD) were impaired in transgenic mice.(4) Behavioral tests showed that NR2A transgenic mice exhibited impaired prefrontal cortex-related working memory and reverse learning in the modified water maze and water maze reverse learning task.Conclusion NR2A/NR2B ratio increasing by NR2A overexpression can shorten the decay time of NMDAR-EPSC and impair prefrontal bidirectional synaptic plasticity and prefrontal cortex-related memory.