Elsevier

Neurobiology of Aging

Volume 25, Issue 2, February 2004, Pages 201-208
Neurobiology of Aging

Changes in the expression of the NR2B subunit during aging in macaque monkeys

https://doi.org/10.1016/S0197-4580(03)00091-5Get rights and content

Abstract

Humans, non-human primates and rodents show declines in spatial memory abilities with increased age. Some of these declines in mice are related to changes in the expression of the epsilon2 (ε2) (NR2B) subunit of the N-methyl-d-aspartate receptor. The purpose of this study was to determine whether primates show changes during aging in the mRNA expression of the NR2B subunit. In situ hybridization was performed on tissue sections from three different ages of Rhesus monkeys (Macaca mulatta; 6–8, 10–12, and 24–26 years). There was a significant decrease in the mRNA expression of the NR2B subunit overall in the prefrontal cortex and in the caudate nucleus between young and old monkeys. There were no significant changes in NR2B mRNA expression in the hippocampus or the parahippocampal gyrus. The results in the prefrontal cortex, caudate and hippocampus were similar to those seen previously in C57BL/6 mice during aging, which suggests that mice may be useful as a model for primates to further examine the age-related changes in the expression of the NR2B subunit of the NMDA receptor in several important regions of the brain.

Introduction

The earliest cognitive declines to be detected in humans during the aging process are in learning and memory functions [4]. Among these memory declines are 30–80% decreases in performance in spatial memory tasks, as compared to young adults [13], [15], [26], [27], [42], [55]. Spatial memory is one cognitive function that is relatively easy to test in animals. Both monkeys [7], [8], [51] and rodents [10], [11], [17], [18], [32], [34], [36], [38], [45], [48], [52], [56] show declines with increased age in performance of spatial memory tasks.

NMDA receptors are important in both reference [21], [40], [43], [44] and working memory tasks [6], [31], [57] that involve spatial memory, as shown by the administration of NMDA receptor antagonists. There are declines in the expression of NMDA receptors with increased age in humans [50], monkeys [19], [62], dogs [35], rats [28], [48], [59], and mice [32], [33], [34]. We have used C57BL/6 mice to examine age-related changes in the NMDA receptor and associated changes in spatial learning and memory abilities [34], [35]. C57BL mice are the most widely used inbred strain of mice in research [16]. The C57BL/6 substrain has a higher than average lifespan [16], [58] and young C57BL/6 mice show good learning ability in spatial memory tasks [5], [61], as compared to other mouse strains. In C57BL/6 mice, the NMDA receptor subunit that is most affected by decreases in mRNA expression with increased age is the epsilon2 (ε2; NR2B in other species) subunit. This age-related change in ε2 mRNA expression shows a relationship with the changes in binding of transmitter glutamate to the receptor [33], [34]. The declines in binding of ligands to the NMDA receptor in the hippocampus and prefrontal/frontal cortex of rodents during aging are associated with reference memory deficits in spatial memory tasks [32], [34], [48]. Changes in both NMDA receptor binding and mRNA expression of the ε2 subunit in prefrontal cortical regions in mice have been shown to be related to working memory deficits in a spatial memory task [9]. Overexpression of the ε2 subunit in the forebrain of mice also provides evidence of the importance of this subunit to spatial memory performance [60]. Because the C57BL/6 mice show declines during aging in spatial memory abilities, both reference and working memory forms, they appear to be a good model for functional declines in human and non-human primates [13], [15], [26], [27], [42], [55]. The purpose of the present study was to determine if primates show declines during aging in the mRNA expression of the NR2B subunit of the NMDA receptor and to determine whether these changes were similar to those we have previously seen in the aged C57BL/6 mouse [33], [34].

Section snippets

Tissue preparation

Rhesus monkeys (Macaca mulatta), consisting of four young adult males (6–8 years of age), two full adult males (10–12 years of age) and one old male and three old females (24–26 years of age) were used in this study. All monkeys were born and raised in captivity and housed in cages for most of their lives. All of the aged monkeys included in the present analysis were retired breeders and none had been involved in any pharmacological or invasive studies. Monthly serological tests, annual

Prefrontal cortex

Inner (layers IV–VI) and outer (layers II–III) cortical layers of prefrontal cortical regions 24, 9, 45, and 12 (Fig. 1) were analyzed separately on each section for average density of hybridization to the NR2B subunit mRNA. The density of binding in white matter within the corona radiata was used to determine non-specific binding. There was a significant main effect of age (F(1,5)=9.528, P=0.0273) on the specific binding density of mRNA for the NR2B subunit over all regions and layers analyzed

Discussion

The results of this study showed a significant decrease with increasing age in the expression of the NR2B subunit of the NMDA receptor in the prefrontal cortex and caudate nucleus of macaque monkeys. There were trends for decreases in the dentate gyrus granule cell layer and the CA3 pyramidal cell layer, but these did not reach significance. There was no noticeable effect of aging on NR2B mRNA expression in other areas of the hippocampus or in the parahippocampal gyrus.

The mRNA expression for

Acknowledgements

Our thanks to Laurie Daggett for providing the cDNA clone and map for the human NR2B plasmid. This work was supported by NIH grants AG16322 to K.R.M., AG05138 to P.R.H. and NS34361 to D.G.S.

References (62)

  • K.R. Magnusson

    The aging of glutamate receptors: correlations between receptor binding and spatial memory performance in C57BL mice

    Mech. Ageing Dev.

    (1998)
  • K.R. Magnusson

    Influence of diet restriction on NMDA receptor subunits and learning during aging

    Neurobiol. Aging

    (2001)
  • A.L. Markowska

    Life-long diet restriction failed to retard cognitive aging in Fischer-344 rats

    Neurobiol. Aging

    (1999)
  • L.W. Means et al.

    Working memory and the aged rat: deficient two-choice win-stay water-escape acquisition and retention

    Physiol. Behav.

    (1991)
  • 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)
  • T.L. Page et al.

    Morphological alterations in neurons forming corticocortical projections in the neocortex of aged Patas monkeys

    Neurosci. Lett.

    (2002)
  • M.A. Piggott et al.

    [3H]MK-801 binding to the NMDA receptor complex, and its modulation in human frontal cortex during development and aging

    Brain Res.

    (1992)
  • G.D. Rudolf et al.

    Expression of N-methyl-d-aspartate glutamate receptor subunits in the prefrontal cortex of the rat

    Neuroscience

    (1996)
  • B. Shukitt-Hale et al.

    Psychomotor and spatial memory performance in aging male Fischer 344 rats

    Exp. Gerontol.

    (1998)
  • M. Tamaru et al.

    Age-related decreases of the N-methyl-d-aspartate receptor complex in the rat cerebral cortex and hippocampus

    Brain Res.

    (1991)
  • G.L. Wenk et al.

    Loss of NMDA, but not GABA-A, binding in the brains of aged rats and monkeys

    Neurobiol. Aging

    (1991)
  • M.M. Adams et al.

    Hippocampal dependent learning ability correlates with N-methyl-d-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats

    J. Comp. Neurol.

    (2001)
  • Albert MS, Funkenstein HH. The effects of age: normal variation and its relation to disease. In: Asbury AK, McKhann GM,...
  • M. Ammassari-Teule et al.

    Learning in inbred mice: strain-specific abilities across three radial maze problems

    Behav. Genet.

    (1993)
  • J. Aura et al.

    Blockade of NMDA receptors located at the dorsomedial prefrontal cortex impairs spatial working memory in rats

    Neuroreport

    (1999)
  • J. Bachevailer

    Behavorial changes in aged rhesus monkeys

    Neurobiol. Aging

    (1993)
  • L. Bai et al.

    Relationships between NMDA receptor expression in prefrontal cortex and spatial reference and working memory during aging

    Soc. Neurosci. Abstr.

    (2002)
  • C.A. Barnes

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

    J. Comp. Physiol. Psychol.

    (1979)
  • K.E. Cherry et al.

    Individual difference and contextual variables influence spatial memory in younger and older animals

    Psychol. Aging

    (1993)
  • G.W.P. Evans et al.

    Cognitive mapping and elderly adults: verbal and location memory for urban landmarks

    J. Gerontol.

    (1984)
  • Festing MFW. Inbred strains of mice: C57BL. Last update: April 1998; access date: Dec 2002,...
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