Increased NMDA receptor GluN2A-type ionotropic signaling is sufficient to improve spatial memory in immature mice

Spatial learning and memory are reliant on activation of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses in the hippocampus. NMDARs at immature synapses contain mostly GluN2B subunits while at mature synapses, more NMDARs contain GluN2A subunits. A hippocampal NMDAR GluN2B to GluN2A subunit shift occurs in rodents during the third postnatal week, permitting rapid and detailed contextual encoding and memory retrieval without a reminder. Adult transgenic mice expressing chimeric GluN2 subunits (carboxy terminal domains swapped between GluN2A and GluN2B, GluN2A-B^CTD or GluN2B-A^CTD) have implicated GluN2A-type ionotropic signaling in spatial context encoding and GluN2B-type carboxy terminal domain (CTD) signaling in memory retrieval. However, the individual contributions of GluN2A and GluN2B subunit ionotropic and CTD signaling to the maturation of spatial learning and memory have not been defined. By increasing GluN2A-type ionotropic signaling in preweanling mice via expression of chimeric GluN2 subunits, we found improved long-term memory in a massed training version of the Morris water maze. These findings suggest that increased GluN2A-type ionotropic signaling enables encoding of spatial context in a manner that permits more mature long-term memory retrieval. These findings support unique contributions from GluN2A- and GluN2B-containing NMDARs that combine to optimize spatial learning and memory.