Grin2b 3UTR is necessary for synaptic plasticity and spatial learning

Spatially precise protein synthesis is critical for synaptic plasticity and cognitive function. The GRIN2B transcript encodes the GluN2B subunit of N-methyl-D-aspartate (NMDA) receptors and has a 25 kb-long 3-untranslated region (3UTR) of unknown function. To investigate its role, we generated a d3UTR mouse line by deleting the Grin2b 3UTR while preserving the coding sequence. Despite unchanged Grin2b mRNA levels in d3UTR mice, GluN2B protein was reduced by half. In wildtype (WT) mice, Grin2b mRNA was enriched in synaptosomes, but this enrichment was impaired in d3UTR mice along with reduced GluN2B phosphorylation. Notably, d3UTR mice had no long-term potentiation (LTP) and exhibited hippocampal-dependent spatial learning impairments. Together, these findings demonstrate that the 3UTR is critical for Grin2b mRNA function, ultimately influencing synaptic composition and plasticity.