Recent evidence indicates that continuous wakefulness (sleep deprivation, SD) causes impairments in behavioral performance and hippocampal long-term potentiation (LTP) in animals. However, the mechanisms by which SD impairs long-term synaptic plasticity and cognitive function are not clear. Here, we report that 24-h SD in mice results in impaired hippocampus-dependent contextual memory and LTP and, unexpectedly, in reductions of the surface expression of NMDA receptor (NMDAR) subunit NR1 and NMDAR-mediated excitatory post-synaptic currents at hippocampal perforant path-dentate granule cell synapses. The results suggest that the reduction of functional NMDAR in hippocampal neurons may underlie the SD-induced deficits in hippocampus-dependent contextual memory and long-term synaptic plasticity.