Aging of glutamate receptors: correlations between binding and spatial memory performance in mice

https://doi.org/10.1016/S0047-6374(98)00076-1Get rights and content

Abstract

C57Bl/6 mice aged 3, 10, and 26 months were tested for spatial learning in the Morris water maze. Ten and 26 month old mice were ad libitum-fed or diet restricted (60% of ad libitum-fed calories). Diet restriction significantly improved memory performance among the 10 and 26 month olds. In age/diet group comparisons, aged ad libitum-fed mice had significantly higher average proximity scores, indicating poorer performance, in probe trials for place learning than the 3 month olds and diet restricted 10 month olds. Diet restricted 26 month olds did not differ significantly from 3 month olds or any other groups in probe trial measures. The group means for average proximity scores were significantly correlated with binding densities for the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors in the frontal cortex and CA1 region of the hippocampus. α-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) binding correlated with group proximity scores in frontal and parietal cortices and within the CA1 and CA3 regions of the hippocampus. Kainate and metabotropic binding sites showed no significant correlations with behavior. These results suggest that there is a sparing of spatial memory with diet restriction in aging C57Bl/6 mice and that the effects of aging on NMDA and AMPA receptors may be associated with age-related declines in spatial learning.

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)

References (46)

  • E.W Harris et al.

    Long-term potentiation in the hippocampus involves activation in N-methyl-d-aspartate receptors

    Brain Res.

    (1984)
  • V Heale et al.

    MK801 and AP5 impair aquisition, but not retention, of the Morris milk maze

    Pharmacol. Biochem. Behav.

    (1990)
  • K.R Magnusson et al.

    Age-related changes in excitatory amino acid receptors in two mouse strains

    Neurobiol. Aging

    (1993)
  • K.R Magnusson

    Differential effects of aging on binding sites of the activated NMDA receptor complex in mice

    Mech. Aging Dev.

    (1995)
  • K.R Magnusson

    Influence of dietary restriction on ionotropic glutamate receptors during aging in C57Bl mice

    Mech. Aging Dev.

    (1997)
  • R.G.M Morris

    Development of a water-maze procedure for studying spatial learning in the rat

    J. Neurosci. Methods

    (1984)
  • R.G.M Morris et al.

    Synaptic plasticity and learning II: do different kinds of plasticity underlie different kinds of learning?

    Neuropsychologia

    (1989)
  • S Nakanishi

    Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity

    Neuron

    (1994)
  • M.M Nicolle et al.

    In vitro autoradiography of ionotropic glutamate receptors in hippocampus and striatum of aged Long–Evans rats: relationship to spatial learning

    Neuroscience

    (1996)
  • J.P Pin et al.

    The metabotropic glutamate receptors: structure and functions

    Neuropharmacology

    (1995)
  • N Pitsikas et al.

    Deterioration of spatial and nonspatial reference and working memory in aged rats: protective effect of life-long calorie restriction

    Neurobiol. Aging

    (1992)
  • G Richter-Levin et al.

    Activation of metabotropic glutamate receptors is necessary for long-term potentiation in the dentate gyrus and for spatial learning

    Neuropharmacology

    (1994)
  • C.A Barnes

    Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat

    J. Comp. Physiol. Psychol.

    (1979)
  • Cited by (104)

    • Attenuated NMDAR signaling on fast-spiking interneurons in prefrontal cortex contributes to age-related decline of cognitive flexibility

      2021, Neuropharmacology
      Citation Excerpt :

      Attenuated N-methyl-d-aspartate receptor (NMDAR) signaling in aging may be one contributor to age-related cognitive deficits as acutely blocking NMDARs with MK-801, phencyclidine or ketamine reliably impairs set-shifting in young adult rats (Blot et al., 2015; Darrah et al., 2008; Egerton et al., 2005; Jett et al., 2017; Nikiforuk et al., 2010; Stefani et al., 2003; Stefani and Moghaddam, 2005, 2010). Consistent with this view, NMDARs are known to decline in PFC aging across humans and rats (Dickstein et al., 2013; Dyall et al., 2007; Hellström-Lindahl and Court, 2000; Magnusson, 1998; Magnusson et al, 2005, 2007; Magnusson and Cotman, 1993; McQuail et al., 2016; Migani et al., 2000; Mitchell and Anderson, 1998; Piggott et al., 1992; Wenk et al., 1991). Critically, activation of PFC NMDARs during cognitively demanding tasks depends on permissive contributions from α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), which may also diminish with age and are implicated in cognitive flexibility (Jett et al., 2017; Magnusson and Cotman, 1993; McQuail et al., 2016; Stefani et al., 2003; Wang et al., 2013).

    • D-serine in physiological and pathological brain aging

      2021, Biochimica et Biophysica Acta - Proteins and Proteomics
    View all citing articles on Scopus
    View full text