The NMDA receptor is an important component of spatial working and reference memory. The receptor is a heterotetramer composed of a family of related subunits. The GluN2B subunit of the NMDA receptor appears to be essential for some forms of memory and is particularly vulnerable to change with age in both the hippocampus and cerebral cortex. GluN2B expression is particularly reduced in frontal cortex synaptic membranes. The current study examined the relationship between spatial cognition and protein-protein interactions of GluN2B-containing NMDA receptors in frontal cortex crude synaptosome from 3, 12, and 26-month-old C57BL/6 mice. Aged mice showed a significant decline in spatial reference memory and reversal learning from both young and middle-aged mice. Coimmunoprecipitation of GluN2B subunits revealed an age-related increase in the ratio of both postsynaptic density-95 (PSD-95) and the GluN2A subunit to the GluN2B subunit. Higher ratios of PSD-95/GluN2B and GAIP-interacting protein C-terminus (GIPC)/GluN2B were associated with poorer learning index scores across all ages. There was a significant correlation between GIPC/GluN2B and PSD-95/GluN2B ratios, but PSD-95/GluN2B and GluN2A/GluN2B ratios did not show a relationship. These results suggest that there were more triheteromeric (GluN2B/GluN2A/GluN1) NMDA receptors in older mice than in young adults, but this did not appear to impact spatial reference memory. Instead, an increased association of GluN2B-containing NMDA receptors with synaptic scaffolding proteins in aged animals may have contributed to the age-related memory declines.
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