Mice carrying a GluN2B protein-truncating variant have altered NMDA receptor subunit composition and their behavior recapitulates patient phenotypes

Abstract Pathogenic variants in GRIN2B , encoding the NMDA receptor (NMDAR) GluN2B subunit, are linked to intellectual disability (ID) and related neurodevelopmental disorders. While most disease-associated variants are missense, protein-truncating variants (PTVs) may cause haploinsufficiency with less severe phenotypes. Here, we characterize a knock-in mouse model carrying the GluN2B-L825Ffs*15 PTV ( Grin2b +/Δ ). Proteomic analysis revealed markedly reduced full-length GluN2B protein and no detectable truncated GluN2B, accompanied by a small compensatory increase in GluN2A. Electrophysiology in hippocampal neurons demonstrated reduced NMDA-induced currents, diminished ifenprodil sensitivity, and accelerated NMDAR-mediated EPSC deactivation, consistent with a shift toward GluN2A-containing receptors. AMPAR-mEPSC amplitudes were increased, indicating altered excitatory synaptic function. Behaviorally, Grin2b +/Δ mice exhibited hypoactivity, increased anxiety in males, and impaired sensorimotor gating in both sexes, while learning, memory, and social behaviors remained largely intact. These results demonstrate that a monoallelic GluN2B PTV alters NMDAR subunit composition and function, producing moderate behavioral effects, and provide insight into mechanisms underlying GRIN2B -associated ID.