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

Abstract

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.

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

“…In addition, although three out of four experiments in our laboratory using a 12-day training period showed that old C57BL/6 mice were impaired in both place training and probe trials. (Magnusson, 1998a, 2001, Das and Magnusson, 2008), one study showed deficits in only the place training trials (Magnusson et al, 2003). This suggests that the place training trials may be more sensitive than probe trials for detecting age-related differences in long-term memory.…”

Effects of ibuprofen on cognition and NMDA receptor subunit expression across aging

“…There was no significant effect of ibuprofen on long-term memory in these mice, however, there was a trend for ibuprofen to worsen performance in the oldest mice in the place trials. In probe trials, used to assess the development of a spatial bias, there were no differences in performance for treatment or age, unlike in other studies (Magnusson et al, 2007, Das and Magnusson, 2008, Das and Magnusson, 2011, Brim et al, 2013, Zamzow et al, 2013), but see (Zhao et al, 2009). Some of the oldest mice were unable to complete all of the place trials in this study.…”

“…The GluN2B subunit (Magnusson, 2000, Magnusson et al, 2002) and GluN1-1 and GluN1-3 splice variants (Magnusson et al, 2005, Das and Magnusson, 2008) have previously been shown to be selectively vulnerable to the effect of aging in C57BL/6 mice. If inflammation was playing a role during aging on NMDA receptors, it was expected that ibuprofen would improve the expression of GluN2B, all GluN1 subunits as a whole, and the GluN1-1 and GluN1-3 splice variants, particularly in the oldest animals, but not affect GluN1-2 splice variants.…”

“…Spatial long-term memory, delayed short-term memory, cognitive flexibility, and cued control task abilities were tested using the Morris water maze as previously described (Das and Magnusson, 2008, Das et al, 2012). A 1.2 m diameter plastic tank was filled with water (16–18°C) that was made an opaque white with non-toxic paint.…”

“…Eight different splice variants of mRNA exist for the GluN1 subunit through alternative splicing of one N-terminal and two C-terminal cassettes, C1 and alternatively C2 or C2′ (Laurie and Seeburg, 1994, Zukin and Bennett, 1995). Studies have found that mRNA for C-terminal splice forms, GluN1-1 (+ C1 and + C2 cassettes) and GluN1-3 (+ C1 and + C2′), show significant declines during aging in several brain regions, even though overall GluN1 mRNA expression is not always significantly affected by aging, suggesting these splice forms are more influenced by aging than the subunit as a whole (Magnusson et al, 2005, Das and Magnusson, 2008). …”