Characterization of the Grin1Q536R/+ mouse: a preclinical model for GRIN1-related neurodevelopmental disorder
- 1University of Toronto
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.
Related
- Myoclonus, Dystonia, and Ataxia in U2AF2 ‐Related Neurodevelopmental Disorder
- Chromodomain Helicase DNA-Binding Domain 8 (CHD8) related neurodevelopmental disorder with overgrowth: a case series and a systematic literature review on neuroradiological findings
- Motor, Postural, and Communicative Phenotype in SHQ1-Related Neurodevelopmental Disorder with Dystonia and Seizures: An Interdisciplinary Case Report and Hypothesis-Generating Physiotherapy Framework.
- Editorial: Potential therapeutic targets in alcohol use disorder: insights from recent preclinical studies
- KCTD3 deficiency disrupts axon initial segment organization and neurite outgrowth in a neurodevelopmental disorder mouse model
BibTeX
@misc{sullivan2026characterization,
title = {{Characterization of the Grin1Q536R/+ mouse: a preclinical model for GRIN1-related neurodevelopmental disorder}},
author = {M. T. Sullivan and Y. Yan and L. Vania and P. Tidball and Q. Pauli and T. V. Lipina and S. Venkatesan and P. B. Finnie and E. Fujiwara and W. Horsfall and J. Georgiou and R. E. McCullumsmith and E. K. Lambe and R. E. Bonin and A. Salahpour and G. L. Collingridge and A. J. Ramsey},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.09.750465},
url = {https://www.biorxiv.org/content/10.64898/2026.09.09.750465v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Characterization of the Grin1Q536R/+ mouse: a preclinical model for GRIN1-related neurodevelopmental disorder
AU - M. T. Sullivan
AU - Y. Yan
AU - L. Vania
AU - P. Tidball
AU - Q. Pauli
AU - T. V. Lipina
AU - S. Venkatesan
AU - P. B. Finnie
AU - E. Fujiwara
AU - W. Horsfall
AU - J. Georgiou
AU - R. E. McCullumsmith
AU - E. K. Lambe
AU - R. E. Bonin
AU - A. Salahpour
AU - G. L. Collingridge
AU - A. J. Ramsey
PY - 2026
DA - 2026/09/09
PB - bioRxiv
DO - 10.64898/2026.09.09.750465
UR - https://www.biorxiv.org/content/10.64898/2026.09.09.750465v1
AB - 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.
ER -