There are declines in the protein expression of the NR2B (mouse ε2) and NR1 (mouse ζ1) 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 & 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 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. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 September 15. Published in final edited form as:Neuroscience. Memory is one of the earliest of the cognitive functions to show declines during aging (Albert and Funkenstein, 1992). Memory deficits associated with aging are seen in humans and nonhuman primates (see reviews Nicolle, 1993, Gallagher andRapp, 1997)), dogs (Head et al., 1995) and rodents (Gage et al., 1984, Rapp et al., 1987, Barnes, 1988, Zyzak et al., 1995. One type of memory that is important for how individuals cope with their environment is spatial memory. Humans show 30% to 80% drops in performance in spatial memor...
The human cytomegalovirus (HCMV) tegument protein UL69 is important for efficient viral replication at low multiplicities of infection. Several molecular mechanisms by which UL69 contributes to HCMV replication have been proposed, including UL69's ability to interact with the mRNA export factors UAP56 and URH49 to facilitate the shuttling of viral mRNAs from the nuclei of infected cells. Using a UL69 viral mutant that is unable to bind UAP56 and URH49, we demonstrated that UL69's interaction with UAP56 or URH49 does not contribute to the growth phenotype associated with the UL69 deletion mutant.Human cytomegalovirus (HCMV) encodes roughly 25 proteins that compose the tegument layer, which resides between the nucleocapsid and the viral envelope. These proteins are packaged within the mature virion, are delivered to the host cell immediately upon infection, and play important roles in entry, gene regulation, immune evasion, DNA replication, virion assembly, and viral egress (8, 9). The UL69 tegument protein has previously been shown to play an important role in regulating efficient replication of HCMV (5). Infection with a UL69 deletion mutant results in a severely multiplicity-dependent growth phenotype (5). However, the mechanism whereby UL69 contributes to viral replication has remained elusive. Previous studies have provided clues as to how UL69 may participate in regulating HCMV replication. Activities associated with UL69 include its ability to regulate cell cycle progression (5, 13), regulate viral gene expression (5), shuttle between the nucleus and cytoplasm (10, 12), bind RNA (19), and interact with itself (11) and several cellular proteins (1,12,16,18,21).UL69 and its herpesvirus homologues are thought to function in part by regulating the export of intronless viral mRNAs from the nucleus to the cytoplasm within infected cells (10,12,20). In support of this, UL69 has been shown to interact with the cellular factors U2AF65-associated protein 56 (UAP56) and the 90% identical UAP56-related helicase 49 (URH49) (12). UAP56 and URH49 are DEAD-box helicases, which are RNA-dependent ATPases that play important roles in connecting pre-mRNA splicing with mature mRNA export (14, 15). The ability of UL69 to bind UAP56 and/or URH49 has been hypothesized to be critical for its ability to promote the export of viral transcripts during infection and to play a critical role in controlling viral replication (12,20). Even though previous studies have clearly demonstrated that UL69 can bind to UAP56 and URH49 and that these interactions are required for the efficient nuclear export of an unspliced reporter gene, the significance of UL69's interaction with UAP56 and/or URH49 has not been determined in the context of a productive viral infection where these proteins are expressed at physiological levels and in the presence of the full complement of viral proteins. Therefore, this study utilizes a UL69 UAP56/ URH49 viral binding mutant to determine if UL69's interaction with UAP56 or URH49 is required for efficient HCMV repli...
Caloric restriction enhances N-methyl-D-aspartate (NMDA) receptor binding and upregulates messenger RNA expression of the GluN1 subunit during aging. Old growth hormone receptor knockout mice resemble old calorically restricted rodents in enhanced life span and brain function, as compared with aged controls. This study examined whether aged growth hormone receptor knockout mice also show enhanced expression of NMDA receptors. Six or 23- to 24-month-old male normal-sized control or dwarf growth hormone receptor knockout mice were assayed for NMDA-displaceable [(3)H]glutamate binding (autoradiography) and GluN1 subunit messenger RNA (in situ hybridization). There was slight sparing of NMDA receptor binding densities within aged medial prefrontal and motor cortices, similar to caloric restriction, but there were greater age-related declines in GluN1 messenger RNA in growth hormone receptor knockout versus control mice. These results suggest that some of the functional improvements in aged mice with altered growth hormone signaling may be due to enhancement of NMDA receptors, but not through the upregulation of messenger RNA for the GluN1 subunit.
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