MK-801 Improves Retention in Aged Rats: Implications for Altered Neural Plasticity in Age-Related Memory Deficits

Abstract

Alterations in N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity, characteristic of aged rodents, may contribute to impaired memory with advanced age. The purpose of the current research was to examine whether NMDARs contribute to rapid forgetting on a spatial memory task. Aged (22-24 months) and adult (3-6 months) male Fischer 344 rats received 18 training trials, over a period of 3 to 4 h, on the spatial version of the Morris water maze. Immediately after training, a standard free-swim probe trial was administered to assess the acquisition of spatial bias, which was determined by the percent of time spent in the goal quadrant and the number of platform crossings. Rats then received injections of the noncompetitive NMDAR antagonist, (ϩ)-10,11-dihydro-5methyl-5H-dibenzo-(a,b)cycloheptene-5,10 imine (MK-801, 0.05 mg/kg, i.p.), or a vehicle injection of equal volume. Approximately 24 h later, rats were administered a second free-swim probe trial to assess retention of spatial bias. All age/drug groups exhibited a spatial bias on the acquisition probe, with adults generally outperforming the aged rats. On the retention probe, this spatial bias continued to be shown by adult rats, regardless of treatment. For the aged group, in contrast, only MK-801-injected rats maintained a spatial bias on the retention probe, suggesting that NMDAR activity may be involved in rapid forgetting during aging. Because blockade of NMDARs also may impair new learning, which may, in turn, protect previously stored information from retroactive interference, rats in a second experiment received post-training injections of scopolamine (0.05 mg/kg), a compound known to inhibit learning. However, scopolamine did not enhance retention in the aged group, consistent with the hypothesis that MK-801 influenced memory in aged rats through its actions on NMDAR-dependent synaptic plasticity.

Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

“…Methods used here for cognition assessment in the SWM, a task sensitive to both hippocampal function and aging, have been described previously (Norris and Foster, 1999). Briefly, rats were trained in a black tank, 1.7 m in diameter, that was filled with water (27 Ϯ 2°C).…”

Calcineurin Links Ca2+Dysregulation with Brain Aging

“…For probe trials in which the platform was removed, differential quadrant search time and platform crossings were recorded. These measures are more sensitive to effects on memory than using latency alone (Norris and Foster, 1999).…”

“…Methods for using the Morris swim task to access sensorimotor and memory deficits have been published previously (Foster et al, 1991;Mabry et al, 1996;Fugger et al, 1997;Norris and Foster, 1999). Animals were trained in a black tank, 1.7 m in diameter, positioned in a well lit room that was painted flat black.…”

“…After completion of five training blocks, acquisition of a spatial search strategy was determined using a free-swim probe trial, which provides a more valid measure of spatial discrimination learning (Foster et al, 1991;Fugger et al, 1997;Norris and Foster, 1999). No age-related differences were observed for time spent in the goal quadrant or the quadrant opposite the goal (Fig.…”

Susceptibility to induction of long-term depression is associated with impaired memory in aged Fischer 344 rats

“…With continued training aged animals improve to a level comparable to that observed in younger animals (Rapp et al 1987), however; in some cases aged animals continue to exhibit deficits, such that aged animals can be categorized as learning impaired and unimpaired. Similarly, when training is massed into a single day, young and aged animals exhibit a similar level of acquisition by the end of training, and a subgroup of aged animals exhibits evidence for memory deficits 24 hr following training (Foster et al 1991;Foster et al 2001;Norris & Foster 1999). The results indicate that, there is considerable individual variability in the extent of learning and memory deficits in aged animals.…”