Reducing expression of GluN10XX subunit splice variants of the NMDA receptor interferes with spatial reference memory

Abstract

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, GluN10XX (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 GluN10XX splice variants are required for good performance in reference memory tasks in young mice. Mice were bilaterally injected with either siRNA specific for GluN10XX 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 GluN10XX splice variants within the ventro-lateral orbital cortices in mice following GluN10XX siRNA treatment. Declines in performance within the first half of reference memory testing were seen in the mice receiving siRNA against the GluN10XX splice variants, as compared to the mice injected with control siRNA, vehicle and/or no treatment. These results suggest a role for the GluN10XX splice variants in orbital regions for early acquisition and/or consolidation of spatial reference memory.

Higher levels of phosphorylated Y1472 on GluN2B subunits in the frontal cortex of aged mice are associated with good spatial reference memory, but not cognitive flexibility

“…Data for behavioral testing were analyzed as previously described (Das et al 2012). Cumulative proximity measures, which reflect search distance from the platform, were used for the place, reversal, and cued trials, and average proximity measures were used for probe trials (Gallagher et al 1993).…”

“…Cumulative proximity measures, which reflect search distance from the platform, were used for the place, reversal, and cued trials, and average proximity measures were used for probe trials (Gallagher et al 1993). Proximity measures were corrected for start position (Das et al 2012). Based on reference memory acquisition performance in the place trials, the old mice were divided into two categories for BReference memory-Good^(RG; N = 7) and BReference memory-Bad^(RB; N = 5) learners as previously described (Lee et al 1994;Rowe et al 2007;Yetimler et al 2012) with some modifications.…”

“…Spatial reference memory, cognitive flexibility, and associative memory (cued control task) were tested with the use of the Morris water maze as previously described (Das et al 2012). Briefly, for the first 2 days, mice were acclimated to the water maze, followed by 2 days of testing for spatial reference memory, 1 day of reversal training to test cognitive flexibility, and 1 day of associative memory testing (cued control task).…”

Xanthohumol improved cognitive flexibility in young mice

“…Spatial reference memory, cognitive flexibility and associative memory (cued control task) were tested with the use of the Morris water maze as previously described [34]. Briefly, for the first two days, mice were acclimated to the water maze, followed by 4 days of testing for spatial reference memory, 1 day of reversal training to test cognitive flexibility and 1 day of associative memory testing (cued control task).…”

The involvement of <italic>N</italic>-methyl-d-aspartate receptor (NMDAR) subunit NR1 in the pathophysiology of schizophrenia

“…For example, chronic developmental Pb 2 + exposure could produce the deficits in synaptic plasticity and in learning in young adult rats by altering the cell surface expression of NMDAR-NR1 subunits (lacking C1 cassettes) [29]. Reduced expression of NR1 splice variants of NMDARs (lacking N terminal splice cassettes) could interfere with spatial reference memory in the aging process [30]. Since NR1 splice variants also affect synaptic plasticity, it is no surprise that changes at their mRNA and protein levels were found in the disease of long-term synaptic plasticity-like chronic pain, as well as in cocaine and alcohol abuse [31,32].…”