Distinct compensatory mechanisms in GRIN2B disease variants

N-methyl-D-aspartate receptors (NMDARs) are central to synaptic transmission and plasticity, and pathogenic GRIN2B variants are increasingly linked to eurodevelopmental disorders. However, how different types of variants affect brain function across levels — from synapses to behaviour — and how the brain compensates for these changes is still not well understood.
To explore this, we studied two complementary mouse models carrying disease-associated GRIN2B variants, a missense variant and a truncation variant, representing different types of NMDAR dysfunction. We used electrophysiology, behavioural testing, and proteomics to compare how these variants affect synaptic function, network activity, and behaviour.
Even though both target the same receptor, the two variants lead to clearly different phenotypes. The missense variant mainly changes receptor function, while the truncation variant reduces receptor expression and alters receptor subunit composition. Comparing the two models reveals that the brain engages different compensatory mechanisms at synaptic and molecular levels, depending on the type of genetic change.
Overall, these findings suggest that different GRIN2B variants trigger distinct adaptive responses across biological scales, helping to link genetic variation to functional outcomes in neurodevelopmental disorders.