Aging of glutamate receptors: correlations between binding and spatial memory performance in mice
Introduction
Spatial learning is one form of memory in which humans show significant impairments as they age (Evans et al., 1984, Barnes et al., 1988, Caplan et al., 1995). This type of memory can be modelled in animals with the use of the Morris water maze (Morris et al., 1984) and aged rodents exhibit similar declines to aged humans in their spatial memory performance when tested in this task (Gage et al., 1984, Pelleymounter et al., 1990, Gallagher et al., 1993). Gallagher and co-workers have developed a protocol for the Morris water maze that is very sensitive to age-related changes in spatial learning in rats and better reflects the accuracy of the animal’s search than more traditional methods of assessing performance (Gallagher et al., 1993). This protocol utilizes average proximity scores during probe trials to evaluate the animal’s memory for the former platform location. This has the major advantage for aging studies of not being as biased by age-related differences in swim speed as are protocols that use escape latency as the measure of performance.
Dietary restriction is an intervention into the aging process that increases both the median and maximum life spans of laboratory animals, apparently by delaying the effects of aging (Masoro et al., 1993, Turturro et al., 1994, Yu et al., 1994). This intervention has also been shown to prevent or decrease age-associated declines in spatial memory performance (Idobro et al., 1987, Algeri et al., 1991, Pitsikas et al., 1992). Although dietary restriction has multisystemic effects and has been shown to delay age-related effects on many different molecules, genes, and systems (Masoro et al., 1993, Turturro et al., 1994, Yu et al., 1994), to our knowledge, only lipofuscin deposition (Idobro et al., 1987) has been studied for associations with the improvements in memory performance induced by the dietary intervention.
Glutamate is the principal excitatory neurotransmitter in the mammalian brain (Fagg et al., 1983, Fonnum et al., 1984). All of the known glutamate receptors appear to play a role in memory processes. The N-methyl-d-aspartate (NMDA) receptor is an important component for spatial learning, as shown by declines in performance that are induced by NMDA antagonists (Alessandri et al., 1989, Morris et al., 1989a, Heale et al., 1990). Long term potentiation or enhancement (LTP or LTE) is believed to be one of the mechanisms subserving memory at the synaptic level (Barnes et al., 1979, Collingridge et al., 1987). Changes in LTP/LTE are associated with changes in spatial memory performance (Barnes et al., 1979, Morris et al., 1989b). NMDA receptors are involved in the initiation of LTP in many regions (Harris et al., 1984, Collingridge et al., 1987, Morris et al., 1989a) and α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA)/kainate receptors are important for the maintenance of LTP (Muller et al., 1988, Davies et al., 1989).
C57Bl/6 mice experience a significant decrease in binding of glutamate to NMDA receptors during aging in most cortical and a few hippocampal regions (Magnusson et al., 1993, Magnusson et al., 1997a). AMPA and kainate receptors show trends for decreased binding with increased age in mice, but are relatively spared compared to the NMDA receptors (Magnusson et al., 1993, Magnusson et al., 1997a). Although spatial learning has been correlated with binding of the NMDA antagonist [(±)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP) in young and old rats (Pelleymounter et al., 1990), to our knowledge, this is the first examination of the relationships between binding density for all of the ionotropic glutamate receptors and spatial memory in different ages of mice.
Another subtype of glutamate receptors, the metabotropic glutamate receptors, mediate their physiologic responses by coupling to intracellular enzymes and second messengers via G proteins (Nakanishi et al., 1994, Pin et al., 1995). These receptors are also involved in various learning and memory processes (Nakanishi et al., 1994, Pin et al., 1995). Two metabotropic binding sites, metabotropic type 1 (met1) and type 2 (met2; formerly designated as non-NMDA, non-kainate, non-quisqualate (NNKQ) sites (Catania et al., 1993), have been identified by [3H]glutamate binding and are distinguished based on differing affinities to quisqualate. The met1 sites exhibit high affinity and met2 sites have low affinity for quisqualate (Catania et al., 1994a, Catania et al., 1994b). The pharmacology, distribution and developmental pattern of the met1 binding sites resemble the mGluR1/mGluR5 receptors, while met2 binding sites resemble the mGluR2/mGluR3 subtypes of metabotropic receptors (Catania et al., 1993, Catania et al., 1994a, Catania et al., 1994b).
With the use of [3H]glutamate binding, we were able to determine that there were trends for decreased binding to met1 sites with increased age, but they were rarely significant within brain regions (Magnusson et al., 1997b). We also found that although met2 binding sites were maintained from 3 to 26 months of age in ad libitum-fed mice, diet restricted animals showed a significant decrease in many regions (Magnusson et al., 1997b). Even though the age-related changes in these receptors could not explain the degree of age-related decline in memory performance seen, we were still interested in whether there was any relationship between these binding sites and spatial memory performance.
The present study was designed to determine whether a spatial memory task that is sensitive to age-related changes in performance in rats could provide a useful protocol for aging studies in mice and whether it could detect the memory-sparing effects of diet restriction that have previously been reported with other protocols (Idobro et al., 1987, Algeri et al., 1991, Pitsikas et al., 1992). We further wanted to determine whether the effects of aging and/or dietary restriction on spatial memory performance might be related to effects on glutamate receptors and which, if any, of these receptors seemed to be most involved.
Section snippets
Subjects
Thirty-five male C57Bl/6NNIA mice were obtained through the National Institute on Aging’s animal colonies. The animals represented five groups, including three age groups (3, 10, and 26 month olds) and two diet groups (ad libitum-fed and diet restricted) in the following breakdown: 12 ×3 month old ad libitum-fed, 6×10 and 26 month old ad libitum-fed and 26 month old diet restricted, and 5×10 month old diet restricted mice. The diet restricted animals were restricted to 60% of ad libitum-fed
Cued trials
There was no significant effect of group in the cued trials, (F(4, 30)=0.67, P=0.62), and no interaction between group and trial day, (F(12, 90)=0.86, P=0.59). There was a significant effect of trial day, (F(3, 90)=38.6, P<0.001). When all groups were combined, there was a significant decrease in the latency to reach the flagged platform between trial days 1 and 2 and between days 3 and 4 (Fig. 1). Every animal showed improvement in latency from the day 1 measurements and had at least one latency
Discussion
There was a significant difference found between age/diet groups of mice on this spatial memory task and a significant sparing effect of diet restriction overall on the middle-aged and older mice. Twenty-six month old ad libitum-fed mice differed significantly from 3 month old and diet restricted 10 month old mice, but their diet restricted, age-matched counterparts did not differ significantly from any other group in average proximity scores from the probe trials. Higher densities of
Conclusion
We were able to adapt a protocol used for spatial memory assessment in aged rats to detect age-related changes in memory performance in C57Bl/6 mice and the memory sparing effects of diet restriction. Performance in this task was correlated with binding to both NMDA and AMPA receptors in brain regions within the rostral cortex and hippocampus that have already been shown to be important for spatial memory. Finally, the effects of diet restriction on the NMDA receptors in these regions appeared
Acknowledgements
The author would like to acknowledge Dr Kenneth T. Shiarella for his acquisition and preliminary analysis of the data and his design for obtaining proximity measurements; Drs Cynthia Toering, Deidre Stoffregen, and Paula Tyler for their assistance with the behavioral testing, and Dr Andrew Bane and Ann Shiarella for their assistance with the statistical analysis. This research was supported by NIH NRSA AG05619 (KTS), FIRST award AG10607 (KRM) and RCDA AG00659 (KRM)
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