Higher levels of GluN1 splice cassettes, C2 and C2', in hippocampus of aged mice were associated with poor spatial reference memory.

Cognitive decline during aging has been linked to changes in the N-methyl-D-aspartate receptor (NMDAR). Age-related changes in the GluN1 splice cassette proteins have been described in crude synaptosomes, but synaptic and extrasynaptic NMDARs have different impacts on synaptic plasticity. The present study examined the association between cognitive function and C-terminal splice cassette proteins, C1, C2, and C2', in different compartments of the synaptic environment. Young and old C57BL/6 male mice were tested for reference memory and cognitive flexibility in the Morris water maze. The older mice were separated into good and poor reference memory groups based on performance during the acquisition phase. The old mice with poor memory acquisition showed increased levels of the C2 protein in the synaptic membrane and the C2' protein in the extrasynaptic membranes in the hippocampus as compared to old mice with good memory or young, respectively. In the frontal cortex, C2 and C2' protein levels in the extrasynaptic membrane were associated with good cognitive flexibility across ages. Thus, although alternative splice forms of the GluN1 subunit appear to contribute to cognitive declines during aging, the complexity of these changes and relationships suggest that interventions involving manipulating splicing of the C-terminal tail of the GluN1 subunit would likely exacerbate memory or cognitive flexibility problems or both in aged individuals.