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

Age-related changes in the protein and mRNA expression of some of the splice forms of the zeta 1 (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 1 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 (zeta 1-1, zeta 1-3, zeta 1-a and zeta 1-b) and mRNA for all known splice forms (zeta 1-pan) were examined by in situ hybridization. mRNA for C-terminal splice forms, zeta 1-1 (+ C1 and + C2 cassettes) and zeta 1-3 (+ C1 and + C2') showed significant declines during aging in several brain regions even though overall zeta 1-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 zeta 1-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 zeta 1-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 1 splice form expression and performance of memory tasks during aging. (C) 2008 Elsevier B.V. All rights reserved.