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