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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    • "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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    ABSTRACT: Brain aging is associated with declines in synaptic function that contribute to memory loss, including reduced postsynaptic response to neurotransmitters and decreased neuronal excitability. To understand how aging affects memory in a simple neural circuit, we studied neuronal proxies of memory for sensitization in mature vs. advanced age Aplysia californica (Aplysia). L-Glutamate- (L-Glu-) evoked excitatory currents were facilitated by the neuromodulator serotonin (5-HT) in sensory neurons (SN) isolated from mature but not aged animals. Activation of protein kinase A (PKA) and protein kinase C (PKC) signaling rescued facilitation of L-Glu currents in aged SN. Similarly, PKA and PKC activators restored increased excitability in aged tail SN. These results suggest that altered synaptic plasticity during aging involves defects in second messenger systems.
    Frontiers in Aging Neuroscience 09/2015; 7:173. DOI:10.3389/fnagi.2015.00173 · 4.00 Impact Factor
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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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    ABSTRACT: Attention deficit hyperactivity disorder (ADHD) is a heterogeneous behavioural disorder that affects 3-15 % of children worldwide. Spontaneously hypertensive rats (SHR) display the major symptoms of ADHD (hyperactivity, impulsivity and poor performance in tasks that require sustained attention) and are widely used to model the disorder. The present study aimed to test the hypothesis that SHR have a diminished capacity to generate ATP required for rapid synchronized neuronal firing, failure of which might lead to disturbances in neurotransmission that could contribute to their ADHD-like behaviour. Duplicate pooled (n = 5) samples of prefrontal cortex and striatum of prepubertal (35-day-old) SHR and Wistar Kyoto (WKY) rats were subjected to iTRAQ labeling and matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS). The MS/MS spectra were analyzed with ProteinPilot using the Ratus ratus database. Proteins detected with >95 % confidence were tested. SHR had decreased levels of several proteins involved in energy metabolism, cytoskeletal structure, myelination and neurotransmitter function when compared to WKY. Differences in protein levels between SHR and WKY were similar in prefrontal cortex and striatum, suggesting global changes in cortico-striato-thalamo-cortical circuits.
    Journal of Molecular Neuroscience 02/2015; 56(3). DOI:10.1007/s12031-015-0491-z · 2.34 Impact Factor
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    • "An initial screen of their subunit expression in hippocampus revealed that klotho elevation specifically increased total protein levels of the NMDAR subunit GluN2B (Figures S4A–S4E), without altering its mRNA (Figure S4F). Interestingly, transgenic overexpression of GluN2B in mice (Cao et al., 2007; Tang et al., 1999) and rats (Wang et al., 2009) enhances cognition, whereas dysfunction of this subunit in humans and mice contributes to cognitive decline in aging (Piggott et al., 1992; Zhao et al., 2009) and AD (Ittner et al., 2010; Li et al., 2011; Sze et al., 2001). In light of these findings and because the enhancement of learning and memory in KL mice resembled that in "
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    ABSTRACT: Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.
    Cell Reports 05/2014; 7(4). DOI:10.1016/j.celrep.2014.03.076 · 8.36 Impact Factor
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