Age-related declines in a two-day reference memory task are associated with changes in NMDA receptor subunits in mice

Young mice showed significant improvement in probe and place learning when reference memory testing was done prior to cued testing. A significant decrease in performance was seen between 3 and 26 months of age with the two-day reference task, regardless of whether cued testing was performed before or after reference memory testing. There was a significant decline in the protein expression of the ε2 and ζ1 subunits of the NMDA receptor and syntaxin in prefrontal/frontal cortex. The subunit changes showed a significant correlation with both place and probe trial performance.The presence of an age-related decline in performance of the reference memory task regardless of when the cued trials were performed suggests that the deficits were due to factors that were unique to the spatial reference memory task. These results also suggest that declines in specific NMDA receptor subunits in the synaptic pool of prefrontal/frontal brain regions contributed to these age-related problems with performing a spatial reference memory task.Memory is one of the earliest of the cognitive functions to show declines during the aging process [1]. Memory deficits associated with aging are seen in humans and non-human primates (see reviews [2,3]), dogs [4] and rodents [5-8]. One type of memory that is important for how individuals cope with their environment is spatial memory. Humans show 30% to 80% drops in performance in spatial memory tasks as they age [9-14]. Mice and rats also exhibit deficits in spatial memory performance during aging [6-8,15-19].Aged C57BL/6 mice show spatial reference memory problems when tested over 12 days in the Morris water maze [17-19]. We were interested in adopting a task that would show age-related deficits in fewer days in order to test drug interventions with the use of osmotic pumps (Durect Corp., Cupertino, CA). The smallest pump available can deliver drug for 3–14 days, but, in addition to the time necessary for behavioral testing, time is also needed fo