Characterization of the Grin1Q536R/+ mouse: a preclinical model for GRIN1-related neurodevelopmental disorder

Abstract

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors playing critical roles in brain development, synaptic plasticity, and cognition. GRIN1-Related Neurodevelopmental Disorder (GRIN1-NDD) is a rare genetic condition caused by pathogenic variations in the GRIN1 gene, which encodes the obligatory subunit of NMDARs. The spectrum of GRIN1 clinical symptoms is hypothesized to result from the functional consequences that different missense variants have on NMDARs. To investigate the disease mechanism in vivo, we generated a novel heterozygous Grin1Q536R/+ knock-in mouse model that carries the identical variation as an adolescent male patient. We describe the clinical presentation of this patient and conduct comprehensive molecular, morphological, electrophysiological, and behavioural characterization in the juvenile, adult, and aging mice. Compared to wildtype littermates, Grin1Q536R/+ mice displayed reduced whole-cell NMDA-induced currents in cortical pyramidal neurons, and reduced NMDAR-mediated synaptic transmission, decreased long-term potentiation, but intact depotentiation at the hippocampal CA1 synapses. Morphological change was observed in the dentate gyrus region of the Grin1Q536R/+ mice. Behavioral phenotyping revealed age- and sex-dependent differences from controls, including hyperlocomotion, reduced muscle strength, and spatial learning deficits. These phenotypes are in line with the clinical manifestations and the relative disease severity of the male patient. The age-dependent phenotypic shift in Grin1Q536R/+ mice highlights the model’s value for investigating GRIN1-NDD disease progression and informing longitudinal monitoring as well as potential therapeutic adjustments with age. Taken together, our findings establish a novel and robust in vivo model for studying NMDAR mechanisms and disease pathology in GRIN1-NDD, while supporting the preclinical development of new therapeutic strategies. Significance statement Based on an adolescent male patient carrying a de novo heterozygous Q536R variant in the GRIN1 gene, we report the creation and comprehensive molecular, electrophysiological and behavioural characterization of the Grin1Q536R/+ mouse model. Our findings reveal that the Q536R/+ variant confers an in vivo phenotype indicative of loss of NMDAR function, particularly deficits in NMDAR-mediated transmission and long-term potentiation. Grin1Q536R/+ mice display neuroanatomical abnormalities and relatively mild behavioural phenotypes, mirroring the observed clinical severity of the patient. The present study contributes a distinct clinically relevant model of GRIN1 variation that represents aspects of the GRIN1-NDD phenotypic spectrum that are poorly studied. Our findings provide insight into disease mechanisms and support the preclinical development of potential therapeutics for GRIN1-NDD.