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<p>Pathogenic variants in <i>GRIN2B</i>, 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 (<i>Grin2b</i><sup>+/Δ</sup>). 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, <i>Grin2b</i><sup>+/Δ</sup> 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 <i>GRIN2B</i>-associated ID.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月30日

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  • Klevinda Fili,
  • Viktor Kuchtiak,
  • Eni Tomovic,
  • Miriam Candelas Serra,
  • Agnieszka Kubik-Zahorodna,
  • Karel Harant,
  • Paulina Bozikova,
  • Jiri Cerny,
  • Miloslav Korinek,
  • Barbora Hrcka Krausova,
  • Vera Abramova,
  • Mark Dobrovolski,
  • Fatma Elzahraa S. Abdel Rahman,
  • Jan Prochazka,
  • Ales Balik,
  • Tereza Smejkalova,
  • Ladislav Vyklicky

摘要

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.