Grin1Y647S/+Mice: A Preclinical Model ofGRIN1-Related Neurodevelopmental Disorder

Abstract

ABSTRACTObjectiveGRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by clinically significant variation in theGRIN1gene, 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 initialin vitroinvestigations of the functional impacts of theGRIN1Y647S variant and examines itsin vivoconsequences in a mouse model.MethodsTo investigatein vitrofunctional impacts of NMDARs containing GluN1-Y647S variant subunits, GluN1-Y647S was co-expressed with wildtype GluN2A or GluN2B subunits inXenopus laevisoocytes and HEK cells.Grin1Y647S/+mice were created by CRISPR-Cas9 endonuclease-mediated transgenesis and the molecular, electrophysiological, and behavioural consequences of the variant were examined.ResultsIn vitro, NMDARs containing GluN1-Y647S show altered sensitivity to endogenous agonists and negative allosteric modulators, and reduced cell surface trafficking.Grin1Y647S/+mice displayed a reduction in whole brain GluN1 levels and deficiency in NMDAR-mediated synaptic transmission in the hippocampus. Behaviourally,Grin1Y647S/+mice exhibited spontaneous seizures, altered vocalizations, muscle strength, sociability, and problem-solving.InterpretationThe Y647S variant confers a complexin vivophenotype, which reflects largely diminished properties of NMDAR function. As a result,Grin1Y647S/+mice display atypical behaviour in domains relevant to the clinical characteristics ofGRIN1-NDD and the individual carrying the variant. Ultimately, the characterization ofGrin1Y647S/+mice accomplished in the present work expands our understanding of the mechanisms underlyingGRIN1-NDD and provides a foundation for the development of novel therapeutics.