Mice: A Preclinical Model of -Related Neurodevelopmental Disorder

Objective: -related neurodevelopmental disorder ( -NDD) is characterized by clinically significant variation in the gene, which encodes the obligatory GluN1 subunit of N-methyl-D-aspartate receptors (NMDARs). The identified p.Tyr647Ser (Y647S) variant - carried by a 33-year-old female with seizures and intellectual disability - is located in the M3 helix in the GluN1 transmembrane domain. This study builds upon initial investigations of the functional impacts of the Y647S variant and examines its consequences in a mouse model.

Methods: To investigate functional impacts of NMDARs containing GluN1-Y647S variant subunits, GluN1-Y647S was co-expressed with wildtype GluN2A or GluN2B subunits in oocytes and HEK cells. mice were created by CRISPR-Cas9 endonuclease-mediated transgenesis and the molecular, electrophysiological, and behavioural consequences of the variant were examined.

Results: , NMDARs containing GluN1-Y647S show altered sensitivity to endogenous agonists and negative allosteric modulators, and reduced cell surface trafficking. mice displayed a reduction in whole brain GluN1 levels and deficiency in NMDAR-mediated synaptic transmission in the hippocampus. Behaviourally, mice exhibited spontaneous seizures, altered vocalizations, muscle strength, sociability, and problem-solving.

Interpretation: The Y647S variant confers a complex phenotype, which reflects largely diminished properties of NMDAR function. As a result, mice display atypical behaviour in domains relevant to the clinical characteristics of -NDD and the individual carrying the variant. Ultimately, the characterization of mice accomplished in the present work expands our understanding of the mechanisms underlying -NDD and provides a foundation for the development of novel therapeutics.