Age-related changes in the protein expression of subunits of the NMDA receptor

Magnusson, Kathy R.; Nelson, Scott E.; Young, Anne B.

doi:10.1016/s0169-328x(01)00344-8

Cited by 116 publications

(101 citation statements)

References 34 publications

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“…Our lab has observed significant effects of aging on ζ1-pan protein expression (Magnusson et al, 2002) and mRNA in frontal cortex (Magnusson, 2000;Magnusson et al, 2005), yet in another study, there was no effect of aging on the ζ1-pan mRNA expression (Magnusson, 2001). This suggests that some factor(s) produce variability in the effects of aging on ζ1-pan.…”

Section: Mrna Expression Of ζ1 Splice Formsmentioning

confidence: 84%

“…There is evidence that the ζ1 subunit of the NMDA receptor shows declines in mRNA and protein expression during the aging process in C57BL/6 mice (Magnusson, 2000;Magnusson et al, 2002), but some studies in the same strain of mice show no change in ζ1 during aging (Magnusson, 2001). One difference between these studies was the addition of a behavioral experience in the later study (Magnusson, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Relationship between mRNA expression of splice forms of the ζ1 subunit of the N-methyl-d-aspartate receptor and spatial memory in aged mice

Das

Magnusson

2008

Brain Research

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Age-related changes in the protein and mRNA expression of some of the splice forms of the ζ1 (NR1) subunit of the NMDA receptor have been seen in mice and rats. The present study was designed to determine whether individual splice forms of the ζ1 subunit of the NMDA receptor within prefrontal/frontal cortical regions contribute to memory deficits during aging and whether experience in learning tasks can influence the expression of the splice forms. mRNA expression of 4 splice forms (ζ1-1, ζ1-3, ζ1-a and ζ1-b) and mRNA for all known splice forms (ζ1-pan) were examined by in situ hybridization. mRNA for C-terminal splice forms, ζ1-1 (+C1 and +C2 cassettes) and ζ1-3 (+C1 and +C2′), showed significant declines during aging in several brain regions even though overall ζ1-pan mRNA expression was not significantly affected by aging. This suggests that these splice forms are more influenced by aging than the subunit as a whole. There was an increase in the expression of ζ1-a (−N1 cassette) splice form in the behaviorally-experienced old mice relative to the younger groups. Old mice with high levels of mRNA expression for the ζ1-a splice form in orbital cortex showed the best performances in the working memory task, but the poorest performances in the cued, associative learning task. These results suggest that there is a complex interaction between ζ1 splice form expression and performance of memory tasks during aging.

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Section: Mrna Expression Of ζ1 Splice Formsmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Relationship between mRNA expression of splice forms of the ζ1 subunit of the N-methyl-d-aspartate receptor and spatial memory in aged mice

Das

Magnusson

2008

Brain Research

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“…However, the neural mechanisms underlying these effects remain to be determined. NR2A subunit-containing NMDA receptors are highly expressed in forebrain regions mediating emotion, such as the hippocampus and amygdala (Law et al, 2003;Magnusson et al, 2002;Sah and Lopez De Armentia, 2003). A simple model would predict that blockade of glutamatergic excitation of the neuronal activity in regions such as the amygdala would reduce emotional reactivity.…”

Section: % Immobilitymentioning

confidence: 99%

“…In addition, NR2A and NR2B subunits are differentially expressed over the course of development, with NR2B predominating in the mouse brain until the end of the second postnatal week (Liu et al, 2004b). In the adult mouse brain, NR2A-and NR2B-containing NMDA receptors are both highly expressed in brain regions implicated in emotion (Law et al, 2003;Magnusson et al, 2002;Sah and Lopez De Armentia, 2003). Determining the differential roles for specific subunit-containing receptors in behavior is hampered by the lack of NR2A subunit selective pharmacological ligands.…”

Section: Introductionmentioning

confidence: 99%

Genetic Inactivation of the NMDA Receptor NR2A Subunit has Anxiolytic- and Antidepressant-Like Effects in Mice

Boyce-Rustay

Holmes

2006

Neuropsychopharmacol

199

126

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There is growing evidence implicating the glutamate system in the pathophysiology and treatment of mood and anxiety disorders. Glutamatergic neurotransmission is mediated by several receptor subfamilies including multiple NMDA receptor subunits (NR2A-D). However, little is currently understood about the specific roles of NMDA subunits in the mediation of emotional behavior due to a lack of subunit-specific ligands. In the present study, we employed a mouse gene-targeting approach to examine the role of the NR2A subunit in the mediation of anxiety-and depressive-related behaviors. Results showed that NR2A knockout (KO) mice exhibit decreased anxiety-like behavior relative to wild-type littermates (WT) across multiple tests (elevated plus maze, light-dark exploration test, novel open field). NR2A KO mice showed antidepressant-like profiles in the forced swim test and tail suspension test, as compared to WT controls. Locomotor activity in the nonaversive environments of the home cage or a familiar open field were normal in the NR2A KO mice, as were gross neurological and sensory functions, including prepulse inhibition of startle. Taken together, these data demonstrate a selective and robust reduction in anxiety-and depression-related behavior in NMDA receptor NR2A subunit KO mice. Present results support a role for the NR2A subunit in the modulation of emotional behaviors in rodents and provide insight into the role of glutamate in the pathophysiology and treatment of mood and anxiety disorders.

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“…The NMDAr is particularly vulnerable to change during aging (Magnusson et al 2010). Protein expression levels of NMDAr subunits decline with age in the hippocampus and frontal cortex (Das and Magnusson 2011;Magnusson et al 2002;Magnusson et al 2007). GluN2B subunit expression declines significantly in most cellular fractions in the hippocampus of aged mice, but there is a more pronounced aging effect in the synaptic membrane, than in the tissue as a whole, in the frontal cortex (Zhao et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Higher levels of phosphorylated Y1472 on GluN2B subunits in the frontal cortex of aged mice are associated with good spatial reference memory, but not cognitive flexibility

Zamzow¹,

Elias

Acosta

et al. 2016

AGE

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The N-methyl-D-aspartate receptor (NMDAr) is particularly vulnerable to aging. The GluN2B subunit of the NMDAr, compared to other NMDAr subunits, suffers the greatest losses of expression in the aging brain, especially in the frontal cortex. While expression levels of GluN2B mRNA and protein in the aged brain are well documented, there has been little investigation into agerelated posttranslational modifications of the subunit. In this study, we explored some of the mechanisms that may promote differences in the NMDAr complex in the frontal cortex of aged animals. Two ages of mice, 3 and 24 months, were behaviorally tested in the Morris water maze. The frontal cortex and hippocampus from each mouse were subjected to differential centrifugation followed by solubilization in Triton X-100. Proteins from Triton-insoluble membranes, Tritonsoluble membranes, and intracellular membranes/ cytosol were examined by Western blot. Higher levels of GluN2B tyrosine 1472 phosphorylation in frontal cortex synaptic fractions of old mice were associated with better reference learning but poorer cognitive flexibility. Levels of GluN2B phosphotyrosine 1336 remained steady, but there were greater levels of the calpain-induced 115 kDa GluN2B cleavage product on extrasynaptic membranes in these old good learners. There was an age-related increase in calpain activity, but it was not associated with better learning. These data highlight a unique aging change for aged mice with good spatial learning that might be detrimental to cognitive flexibility. This study also suggests that higher levels of truncated GluN2B on extrasynaptic membranes are not deleterious to spatial memory in aged mice.

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Age-related changes in the protein expression of subunits of the NMDA receptor

Cited by 116 publications

References 34 publications

Relationship between mRNA expression of splice forms of the ζ1 subunit of the N-methyl-d-aspartate receptor and spatial memory in aged mice

Relationship between mRNA expression of splice forms of the ζ1 subunit of the N-methyl-d-aspartate receptor and spatial memory in aged mice

Genetic Inactivation of the NMDA Receptor NR2A Subunit has Anxiolytic- and Antidepressant-Like Effects in Mice

Higher levels of phosphorylated Y1472 on GluN2B subunits in the frontal cortex of aged mice are associated with good spatial reference memory, but not cognitive flexibility

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