Reducing expression of GluN1 _0XX subunit splice variants of the NMDA receptor interferes with spatial reference memory

The GluN1 subunit of the N-methyl-d-aspartate (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, GluN1 _0XX (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 GluN1 _0XX splice variants are required for good performance in reference memory tasks in young mice. Mice were bilaterally injected with either siRNA specific for GluN1 _0XX 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 four days in the Morris water maze. There was a 10-19% reduction in mRNA expression for GluN1 _0XX splice variants within the ventro-lateral orbital cortices in mice following GluN1 _0XX siRNA treatment. Declines in performance within the first half of reference memory testing were seen in the mice receiving siRNA against the GluN1 _0XX splice variants, as compared to the mice injected with control siRNA, vehicle and/or no treatment. These results suggest a role for the GluN1 _0XX splice variants in orbital regions for early acquisition and/or consolidation of spatial reference memory.