Selective Vulnerabilities of N-methyl-D-aspartate (NMDA) Receptors During Brain Aging

N-methyl-D-aspartate (NMDA) receptors are present in high density within the cerebral cortex and hippocampus and play an important role in learning and memory. NMDA receptors are negatively affected by aging, but these effects are not uniform in many different ways. This review discusses the selective age-related vulnerabilities of different binding sites of the NMDA receptor complex, different subunits that comprise the complex, and the expression and functions of the receptor within different brain regions. Spatial reference, passive avoidance, and working memory, as well as place field stability and expansion all involve NMDA receptors. Aged animals show deficiencies in these functions, as compared to young, and some studies have identified an association between age-associated changes in the expression of NMDA receptors and poor memory performance. A number of diet and drug interventions have shown potential for reversing or slowing the effects of aging on the NMDA receptor. On the other hand, there is mounting evidence that the NMDA receptors that remain within aged individuals are not always associated with good cognitive functioning. This may be due to a compensatory response of neurons to the decline in NMDA receptor expression or a change in the subunit composition of the remaining receptors. These studies suggest that developing treatments that are aimed at preventing or reversing the effects of aging on the NMDA receptor may aid in ameliorating the memory declines that are associated with aging. However, we need to be mindful of the possibility that there may also be negative consequences in aged individuals

A pro-inflammatory agent, Lipopolysaccharide, can mimic the effects ofaging on spatial reference memory

A pro-inflammatory agent, lipopolysaccharide, can mimic the effects of aging on spatial reference memory E. R. ESCOBEDO and K. R. Magnusson, Dept. of Biomedical Sciences, Coll. of Vet. Med., Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 Humans and rodents experience declines in reference (long-term), working (short-term) memory, and cognitive flexibility during the aging process. Aging changes in GluN1 and GluN2B subunits of N-methyl-D-aspartate (NMDA) receptors show a relationship to both reference and working memory deficits. Sulindac, an anti-inflammatory drug, enhances working memory and NMDA receptor subunit expression in rats. The hypothesis addressed in the present study was that inflammation plays a role in NMDA receptor aging and memory declines. The question addressed was whether a pro-inflammatory treatment in young mice would produce the same changes in memory and NMDA receptor expression as aging. Male C57BL/6 mice (3 month old) were randomly assigned to 2 treatment groups, lipopolysaccharide (LPS) or saline. Non-surgical (24 month old) mice were also included. Cannulas attached to osmotic pumps were implanted into the lateral ventricles of the brain for 3 weeks. One week after pumps were removed, behavioral testing was performed with the Morris water maze. LPS-treated young (cumulative proximity (cm): 6287 ± 625; RANOVA & Fisher’s LSD) performed significantly worse than saline young (Mean: 4565 ± 352) and similar to old mice (Mean: 7519 ± 389) in reference memory place trials. LPS treated young (average proximity (cm): 40 ± 1.4) performed similar to saline young (35 ± 1.3), and old (45± 1.5) performed the poorest in probe trials for reference memory. LPS didn’t appear to have any effect on reversals, working memory, or cued trials. The average swim speed for reference memory and cued trials showed that the LPS treated were the fastest swimmers, presenting that any deficits were not due to poor motor ability. Stimulating inflammation in a young brain produced only some of the memory deficits seen in aging. Supported by NIH grant AG016322 to K.R.M

An Increase in the Association of GluN2B Containing NMDA Receptors with Membrane Scaffolding Proteins Was Related to Memory Declines during Aging

The NMDA receptor is an important component of spatial working and reference memory. The receptor is a heterotetramer composed of a family of related subunits. The GluN2B subunit of the NMDA receptor appears to be essential for some forms of memory and is particularly vulnerable to change with age in both the hippocampus and cerebral cortex. GluN2B expression is particularly reduced in frontal cortex synaptic membranes. The current study examined the relationship between spatial cognition and protein-protein interactions of GluN2B-containing NMDA receptors in frontal cortex crude synaptosome from 3, 12, and 26-month-old C57BL/6 mice. Aged mice showed a significant decline in spatial reference memory and reversal learning from both young and middle-aged mice. Coimmunoprecipitation of GluN2B subunits revealed an age-related increase in the ratio of both postsynaptic density-95 (PSD-95) and the GluN2A subunit to the GluN2B subunit. Higher ratios of PSD-95/GluN2B and GAIP-interacting protein C-terminus (GIPC)/GluN2B were associated with poorer learning index scores across all ages. There was a significant correlation between GIPC/GluN2B and PSD-95/GluN2B ratios, but PSD-95/GluN2B and GluN2A/GluN2B ratios did not show a relationship. These results suggest that there were more triheteromeric (GluN2B/GluN2A/GluN1) NMDA receptors in older mice than in young adults, but this did not appear to impact spatial reference memory. Instead, an increased association of GluN2B-containing NMDA receptors with synaptic scaffolding proteins in aged animals may have contributed to the age-related memory declines.This is the publisher’s final pdf. The published article is copyrighted by Society for Neuroscience and can be found at: http://www.jneurosci.org/.Keywords: Mice, Long term potentiation, Binding, Expression, Subunits, Determinants, Performance, Glutamate receptors, PSD-95, traffickin

Xanthohumol improved cognitive flexibility in young mice

The protein palmitoylation cycle has been shown to be important for protein signaling and synaptic plasticity. Data from our lab showed a change in the palmitoylation status of certain proteins with age. A greater percentage of the NMDA receptor subunits GluN2A and GluN2B, along with Fyn and PSD95 proteins, were palmitoylated in the old mice. The higher level of protein palmitoylation was also associated with poorer learning scores. Xanthohumol is a prenylated flavonoid that has been shown to increase beta-oxidation in the livers of rodents, decreasing circulating free fatty acids in the serum. What is not known is whether the application of xanthohumol could influence the palmitoylation status of proteins. In this study, young and old mice were fed a diet supplemented with xanthohumol for 8 weeks. Spatial memory was assessed with the Morris water maze and protein palmitoylation quantified. The young xanthohumol-treated mice showed a significant improvement in cognitive flexibility. However, this appeared to be associated with the young control mice, on a defined, phytoestrogen-deficient diet, performing as poorly as the old mice and xanthohumol reversing this effect. The old mice receiving xanthohumol did not significantly improve their learning scores. Xanthohumol treatment was unable to affect the palmitoylation of NMDA receptor subunits and associated proteins assessed in this study. This evidence suggests that xanthohumol may play a role in improving cognitive flexibility in young animals, but it appears to be ineffective in adjusting the palmitoylation status of neuronal proteins in aged individuals.Keywords: Palmitoylation, Reversal trials, Aging, Memory, PalmitateKeywords: Palmitoylation, Reversal trials, Aging, Memory, Palmitat

Reducing expression of GluN1OXX subunit splice variants of the NMDA receptor interferes with spatial reference memory

The GluN1 subunit of the NMDA receptor shows age-related changes in its expression pattern, some of which correlate with spatial memory performance in mice. Aged C57BL/6 mice show an age-related increase in mRNA expression of GluN1 subunit splice variants that lack the N terminal splice cassette, GluN1ₒₓₓ (GluN1-a). This increase in expression is associated with good performance in reference and working memory tasks. The present study was undertaken to determine if GluN1ₒₓₓ splice variants are required for good performance in reference memory tasks in young mice. Mice were bilaterally injected with either siRNA specific for GluN1ₒₓₓ splice variants, control siRNA or vehicle alone into ventro-lateral orbital cortices. A fourth group of mice did not receive any injections. Starting five days post-injection, mice were tested for their performance in spatial reference memory, associative memory and cognitive flexibility tasks over 4 days in the Morris water maze. There was a 10 -19% reduction in mRNA expression for GluN1ₒₓₓ splice variants within the ventro-lateral orbital cortices in mice following GluN1ₒₓₓ siRNA treatment. Declines in performance within the first half of reference memory testing were seen in the mice receiving siRNA against the GluN1ₒₓₓ splice variants, as compared to the mice injected with control siRNA, vehicle and/or no treatment. These results suggest a role for the GluN1ₒₓₓ splice variants in orbital regions for early acquisition and/or consolidation of spatial reference memory.Keywords: NMDA receptor, siRNA, Memory, NR1, Splice variant, Zeta

Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells

Sjögren’s disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren’s cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.Research reported in this publication was supported by the National Institutes of Health (NIH): R01AR073855 (C.J.L.), R01AR065953 (C.J.L.), R01AR074310 (A.D.F.), P50AR060804 (K.L.S.), R01AR050782 (K.L.S), R01DE018209 (K.L.S.), R33AR076803 (I.A.), R21AR079089 (I.A.); NIDCR Sjögren’s Syndrome Clinic and Salivary Disorders Unit were supported by NIDCR Division of Intramural Research at the National Institutes of Health funds - Z01-DE000704 (B.W.); Birmingham NIHR Biomedical Research Centre (S.J.B.); Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2155 – Projektnummer 390874280 (T.W.); Research Council of Norway (Oslo, Norway) – Grant 240421 (TR.R.), 316120 (M.W-H.); Western Norway Regional Health Authority (Helse Vest) – 911807, 912043 (R.O.); Swedish Research Council for Medicine and Health (L.R., G.N., M.W-H.); Swedish Rheumatism Association (L.R., G.N., M.W-H.); King Gustav V’s 80-year Foundation (G.N.); Swedish Society of Medicine (L.R., G.N., M.W-H.); Swedish Cancer Society (E.B.); Sjögren’s Syndrome Foundation (K.L.S.); Phileona Foundation (K.L.S.). The Stockholm County Council (M.W-H.); The Swedish Twin Registry is managed through the Swedish Research Council - Grant 2017-000641. The French ASSESS (Atteinte Systémique et Evolution des patients atteints de Syndrome de Sjögren primitive) was sponsored by Assistance Publique-Hôpitaux de Paris (Ministry of Health, PHRC 2006 P060228) and the French society of Rheumatology (X.M.).publishedVersio

Rare X chromosome abnormalities in systemic lupus erythematosus and Sjögren's syndrome

Objective: Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) are related by clinical and serologic manifestations as well as genetic risks. Both diseases are more commonly found in women than in men, at a ratio of ~10 to 1. Common X chromosome aneuploidies, 47,XXY and 47,XXX, are enriched among men and women, respectively, in either disease, suggesting a dose effect on the X chromosome. Methods: We examined cohorts of SS and SLE patients by constructing intensity plots of X chromosome single-nucleotide polymorphism alleles, along with determining the karyotype of selected patients. Results: Among ~2,500 women with SLE, we found 3 patients with a triple mosaic, consisting of 45,X/46,XX/47,XXX. Among ~2,100 women with SS, 1 patient had 45,X/46,XX/47,XXX, with a triplication of the distal p arm of the X chromosome in the 47,XXX cells. Neither the triple mosaic nor the partial triplication was found among the controls. In another SS cohort, we found a mother/daughter pair with partial triplication of this same region of the X chromosome. The triple mosaic occurs in ~1 in 25,000–50,000 live female births, while partial triplications are even rarer. Conclusion: Very rare X chromosome abnormalities are present among patients with either SS or SLE and may inform the location of a gene(s) that mediates an X dose effect, as well as critical cell types in which such an effect is operative. © 2017, American College of Rheumatolog