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Preprint WatchModerateSeptember 16th, 2026

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

Sullivan, M. T.; Yan, Y.; Vania, L.; Tidball, P.; Pauli, Q.; Lipina, T. V.; Venkatesan, S.; Finnie, P. B.; Fujiwara, E.; Horsfall, W.; Georgiou, J.; McCullumsmith, R. E.; Lambe, E. K.; Bonin, R. E.; Salahpour, A.; Collingridge, G. L.; Ramsey, A. J.

A heterozygous Grin1 Q536R knock-in mouse reproduces patient phenotypes through reduced NMDAR-mediated current and synaptic transmission and decreased long-term potentiation, establishing an in vivo model to support preclinical development of NMDAR-directed therapeutics.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The match here is the gene and not the therapeutic hypothesis, and the flag should be read that way. This preprint characterises a loss-of-function GRIN1 variant model of a rare neurodevelopmental disorder and argues for NMDAR-directed therapeutics that would restore receptor function. The single matching Claidex claim, esmethadone in major depressive disorder (esmethadone-grin1-nmda-major-depressive-disorder-phase3-efficacy-failure), is a Phase 3 efficacy failure of an NMDAR channel blocker in a common psychiatric indication, which is the opposite pharmacological direction in a different disease with a different genetic basis. The transferable caution is narrower than the severity band suggests. NMDAR-directed programmes have repeatedly failed to convert electrophysiological effects into clinical benefit, and this model is characterised entirely on electrophysiological and behavioural readouts in mice. A programme built on it should define in advance which human readout would count as evidence of restored receptor function, because the failed precedent in the graph had target engagement and no efficacy.

Abstract excerpt

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.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.