An increase in the association of GluN2B containing NMDA receptors with membrane scaffolding proteins was related to memory declines during aging.

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.

Reducing expression of GluN1(0XX) subunit splice variants of the NMDA receptor interferes with spatial reference memory.

The GluN1 subunit of the N-methyl-D-aspartate (NMDA) receptor shows age-related changes in its expression pattern, some of which correlate with spatial memory performance in mice. Aged C57BL/6 mice show an age-related increase in mRNA expression of GluN1 subunit splice variants that lack the N terminal splice cassette, GluN1(0XX) (GluN1-a). This increase in expression is associated with good performance in reference and working memory tasks. The present study was undertaken to determine if GluN1(0XX) splice variants are required for good performance in reference memory tasks in young mice. Mice were bilaterally injected with either siRNA specific for GluN1(0XX) splice variants, control siRNA or vehicle alone into ventro-lateral orbital cortices. A fourth group of mice did not receive any injections. Starting five days post-injection, mice were tested for their performance in spatial reference memory, associative memory and cognitive flexibility tasks over four days in the Morris water maze. There was a 10-19% reduction in mRNA expression for GluN1(0XX) splice variants within the ventro-lateral orbital cortices in mice following GluN1(0XX) siRNA treatment. Declines in performance within the first half of reference memory testing were seen in the mice receiving siRNA against the GluN1(0XX) splice variants, as compared to the mice injected with control siRNA, vehicle and/or no treatment. These results suggest a role for the GluN1(0XX) splice variants in orbital regions for early acquisition and/or consolidation of spatial reference memory.