Phenotype of mice carrying an NMDA receptor GluN2B protein-truncating variant associated with intellectual disability
Fili, K.; Kuchtiak, V.; Tomovic, E.; Candelas Serra, M.; Kubik-Zahorodna, A.; Harant, K.; Bozikova, P.; Cerny, J.; Korinek, M.; Hrcka Krausova, B.; Abramova, V.; Dobrovolski, M.; Abdel Rahman, F. E. S.; Prochazka, J.; Balik, A.; Smejkalova, T.; Vyklicky, L.
Show 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+/{Delta}). Proteomic analysis revealed markedly reduced full-length GluN2B protein and no detectable truncated GluN2B, accompanied by a 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+/{Delta} 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.
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