The effects of aging on N-methyl-D-aspartate receptor subunits in the synaptic membrane and relationships to long-term spatial memory

Department of Biomedical Sciences, College of Veterinary Medicine, Program in Molecular and Cellular Biology, Center for Healthy Aging, 105 Magruder Hall, Oregon State University, Corvallis, OR 97331-4804, USA.
Neuroscience (Impact Factor: 3.36). 06/2009; 162(4):933-45. DOI: 10.1016/j.neuroscience.2009.05.018
Source: PubMed


There are declines in the protein expression of the NR2B (mouse epsilon2) and NR1 (mouse zeta1) subunits of the N-methyl-D-aspartate (NMDA) receptor in the cerebral cortex and hippocampus during aging in C57BL/6 mice. This study was designed to determine if there is a greater effect of aging on subunit expression and a stronger relationship between long-term spatial memory and subunit expression within the synaptic membrane than in the cell as a whole. Male, C57BL/6JNIA mice (4, 11 and 26 months old) were tested for long-term spatial memory in the Morris water maze. Frontal cortex, including prefrontal regions, and hippocampus were homogenized and fractionated into light and synaptosomal membrane fractions. Western blots were used to analyze protein expression of NR2B and NR1 subunits of the NMDA receptor. Old mice performed significantly worse than other ages in the spatial task. In the frontal cortex, the protein levels of the NR2B subunit showed a greater decline with aging in the synaptic membrane fraction than in the whole homogenate, while in the hippocampus a similar age-related decline was observed in both fractions. There were no significant effects of aging on the expression of the NR1 subunit. Within the middle-aged mouse group, higher expression of both NR2B and NR1 subunits in the synaptic membrane of the hippocampus was associated with better memory. In the aged mice, however, higher expression of both subunits was associated with poorer memory. These results indicate that aging could be altering the localization of the NR2B subunit to the synaptic membrane within the frontal cortex. The correlational results suggest that NMDA receptor functions, receptor subunit composition, and/or the environment in which the receptor interacted in the hippocampus were not the same in the old animals as in younger mice and this may have contributed to memory declines during aging.

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    • "Currently, it is not well known how the multiple subunits of NMDA receptors change with advancing age and how this change may influence the cognitive function. However, evidence is mounting to indicate that advanced age is associated with a decline in NMDA receptor function and subunit expression within brain regions involved in higher brain function including synaptic plasticity, learning and memory (Gonzales et al., 1991; Pittaluga et al., 1993; Barnes et al., 1997; Magnusson, 1998a; Eckles-Smith et al., 2000; Gore et al., 2002; Liu et al., 2008a; Zhao et al., 2009). Possibly the strongest evidence for impairment in NMDA receptor function comes from physiological studies indicate the NMDA receptor mediated excitatory post-synaptic potentials in the Schaeffer collateral pathway of the hippocampus are reduced by approximately 50– 60% in aged animals (Figure 2; Barnes et al., 1997; Eckles-Smith et al., 2000; Billard and Rouaud, 2007; Bodhinathan et al., 2010a; Brim et al., 2013; Kumar and Foster, 2013; Lee et al., 2014). "
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    ABSTRACT: N-methyl-D-aspartate (NMDA) receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. These receptors are tetrameric ion channels composed of a family of related subunits. One of the hallmarks of the aging human population is a decline in cognitive function; studies in the past couple of years have demonstrated deterioration in NMDA receptor subunit expression and function with advancing age. However, a direct relationship between impaired memory function and a decline in NMDA receptors is still ambiguous. Recent studies indicate a link between an age-associated NMDA receptor hypofunction and memory impairment and provide evidence that age-associated enhanced oxidative stress might be contributing to the alterations associated with senescence. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between age-associated impaired cognitive faculties and NMDA receptor hypofunction. The current review intends to present an overview of the research findings regarding changes in expression of various NMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function.
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    • "Studies have shown a decrease in L-Glumediated excitatory transmission during aging corresponding to changes in the composition of subunits of major iGluR including alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPAR) and N-methyl-D-aspartate receptors (NMDAR; Barnes et al., 1992, 1997; Jouvenceau et al., 1998; Magnusson, 1998; Magnusson et al., 2000; Potier et al., 2000; Brim et al., 2013). Specifically, age-related declines in NMDAR binding density and expression of NMDAR subunits in the frontal lobe and hippocampus of rodents were associated with declines in spatial memory during aging (Magnusson et al., 2007; Zhao et al., 2009). The consequences of these changes in iGluR function during aging are decreased synaptic strength resulting in changes in cellular analogs of learning and memory including reduced induction and maintenance of long-term potentiation and lower thresholds for long-term depression (Foster, 1999; Eckles-Smith et al., 2000; Billard and Rouaud, 2007; Bodhinathan et al., 2010; Kumar and Foster, 2013; Lee et al., 2014; Guidi et al., 2015). "
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    • "Jensen et al. (2009) showed that SHR have an NMDA GluR2B component of hippocampal long-term potentiation (LTP) that was not found in agematched Wistar-Kyoto (WKY) rats. The GluR2B component of LTP normally diminishes with aging and therefore the presence of higher levels of functional GluR2B-con- taining NMDA receptors in SHR brains is consistent with a maturational delay in the development of neuronal networks (Zhao et al. 2009). Interestingly, the norepinephrine transporter inhibitor atomoxetine, a drug frequently used to treat children with ADHD, reduced the GluR2B subunit in the striatum and hippocampus of a rat brain, further implicating persistent elevation of GluR2B subunit function in ADHD (Udvardi et al. 2013). "
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