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Characterization of Mice Carrying a Neurodevelopmental Disease-Associated GluN2B(L825V) Variant.

Author information

Affiliations

  • 1. Institute of Physiology of the Czech Academy of Sciences, Prague 14220, Czech Republic.
      Authors
    • Candelas Serra M 1
    • Kuchtiak V 1
    • Kysilov B 1
    • Fili K 1
    • Hrcka Krausova B 1
    • Abramova V 1
    • Dobrovolski M 1
    • Cerny J 1
    • Balik A 1
    (9 authors)
  • 2. Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec 25050, Czech Republic.
      Authors
    • Kubik-Zahorodna A 2
    • Prochazka J 2
    • Kasparek P 2
    • Sedlacek R 2
    (4 authors)
  • 3. Proteomics Core Facility, Faculty of Science, Charles University, Biocev, Vestec 25050, Czech Republic.
      Authors
    • Harant K 3
    (1 author)
  • 4. Institute of Biotechnology of the Czech Academy of Sciences, Vestec 25050, Czech Republic.
      Authors
    • Bozikova P 4
    (1 author)
  • 5. Institute of Physiology of the Czech Academy of Sciences, Prague 14220, Czech Republic
      Authors
    • Smejkalova T 5
    • Vyklicky L 5
    (2 authors)

ORCIDs linked to this article

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 31 Jul 2024, 44(31):e2291232024
https://doi.org/10.1523/jneurosci.2291-23.2024 PMID: 38926089 

Free full text available after 31 Jan 2025

Abstract 

N-Methyl-d-aspartate receptors (NMDARs), encoded by GRIN genes, are ionotropic glutamate receptors playing a critical role in synaptic transmission, plasticity, and synapse development. Genome sequence analyses have identified variants in GRIN genes in patients with neurodevelopmental disorders, but the underlying disease mechanisms are not well understood. Here, we have created and evaluated a transgenic mouse line carrying a missense variant Grin2bL825V , corresponding to a de novo GRIN2B variant encoding GluN2B(L825V) found in a patient with intellectual disability (ID) and autism spectrum disorder (ASD). We used HEK293T cells expressing recombinant receptors and primary hippocampal neurons prepared from heterozygous Grin2bL825V/+ (L825V/+) and wild-type (WT) Grin2b+/+ (+/+) male and female mice to assess the functional impact of the variant. Whole-cell NMDAR currents were reduced in neurons from L825V/+ compared with +/+ mice. The peak amplitude of NMDAR-mediated evoked excitatory postsynaptic currents (NMDAR-eEPSCs) was unchanged, but NMDAR-eEPSCs in L825V/+ neurons had faster deactivation compared with +/+ neurons and were less sensitive to a GluN2B-selective antagonist ifenprodil. Together, these results suggest a decreased functional contribution of GluN2B subunits to synaptic NMDAR currents in hippocampal neurons from L825V/+ mice. The analysis of the GluN2B(L825V) subunit surface expression and synaptic localization revealed no differences compared with WT GluN2B. Behavioral testing of mice of both sexes demonstrated hypoactivity, anxiety, and impaired sensorimotor gating in the L825V/+ strain, particularly affecting males, as well as cognitive symptoms. The heterozygous L825V/+ mouse offers a clinically relevant model of GRIN2B-related ID/ASD, and our results suggest synaptic-level functional changes that may contribute to neurodevelopmental pathology.

Full text links 

Read article at publisher's site: https://doi.org/10.1523/jneurosci.2291-23.2024

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    Funding 

    Funders who supported this work.

    Czech Science Foundation (1)

    Grant Agency of Charles University (1)

    Ministry of Education, Youth and Sport of the Czech Republic (1)

    National Sustainability Program II (1)

    Research Project of the CAS RVO (3)