Biology subjects

Horsfall, W.

Publications and source records attributed to Horsfall, W..

3 recordsLinked to original sources

bioRxiv2026

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

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.

neuroscience↗

bioRxiv2024

Grin1Y647S/+ Mice: A Preclinical Model of GRIN1-Related Neurodevelopmental Disorder

GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by clinically significant variation in the GRIN1 gene, which encodes the obligatory GluN1 subunit of N-methyl-D-aspartate receptors (NMDARs). The identified p.Tyr647Ser (Y647S) variant is carried by a 34-year-old female with seizures and intellectual disability. This study builds upon initial in vitro investigations of the functional impacts of this variant in the SYTANLAAF domain of the GluN1 M3 helix and examines its in vivo consequences in a mouse model. To investigate in vitro functional impacts of NMDARs containing GluN1-Y647S variant subunits, GluN1-Y647S was co-expressed with wildtype GluN2A or GluN2B subunits in Xenopus laevis oocytes 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. Additionally, de-identified patient data were collected to examine the representative nature of Grin1Y647S/+ mice in modelling specific aspects of patient symptomology. In vitro, NMDARs containing GluN1-Y647S showed altered sensitivity to endogenous agonists and negative allosteric modulators, and reduced cell surface trafficking. Ex vivo, Grin1Y647S/+ mice displayed a reduction in whole brain GluN1 levels and a deficiency in NMDAR-mediated synaptic transmission in the hippocampus. Behaviourally, Grin1Y647S/+ mice exhibited altered vocalizations, muscle strength, sociability, and problem-solving, as well as spontaneous convulsions that were ameliorated with supplementation of {beta}-hydroxybutyrate (BHB), an endogenously produced ketone body. The Y647S variant confers a complex in vivo phenotype, which reflects largely diminished properties of NMDAR function. As a result, Grin1Y647S/+ mice display atypical behaviour in domains relevant to the clinical characteristics of GRIN1-NDD and the individual carrying the variant, which allowed for the identification of BHB supplementation as a potential anti-convulsant treatment. Ultimately, the characterization of Grin1Y647S/+ mice accomplished in the present work, expands our understanding of the mechanisms underlying GRIN1-NDD and provides a foundation for the continued development of novel therapeutics.

neuroscience↗

bioRxiv2017

Consequences Of NMDA Receptor Deficiency Can Be Rescued In The Adult Brain

N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signaling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 is restored to wildtype by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive behaviors, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.

neuroscience↗