Down-regulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation

NR3A is the only NMDA receptor (NMDAR) subunit that down-regulates sharply prior to the onset of sensitive periods for plasticity, yet the functional importance of this transient expression remains largely unknown. To investigate the possibility that removal/replacement of juvenile NR3A-containing NMDARs is involved in experience-driven synapse maturation, we used a reversible transgenic system that allowed persistent NR3A expression in the postnatal forebrain. We found that removal of NR3A is required to develop strong NMDAR currents, full expression of long-term synaptic plasticity, a mature synaptic organization characterized by more synapses and larger postsynaptic densities, and the ability to form long-term memories. Deficits associated with prolonged NR3A were reversible, as late-onset suppression of transgene expression rescued both the synaptic and memory impairments. Our results suggest that NR3A behaves as a molecular brake to prevent the premature strengthening and stabilization of excitatory synapses, and that NR3A removal might thereby initiate critical stages of synapse maturation during early postnatal neural development.