Neurodevelopmental disorder‐causing <scp>GRIN1 Y647S</scp> variant alters red blood cell physiology in mice

GRIN Disorder is a rare neurodevelopmental disease caused by pathogenic variants in GRIN genes encoding subunits of the N-methyl-D-aspartate receptor (NMDAR). GRIN Disorder presents with a wide spectrum of neurological symptoms and currently lacks effective therapeutics and clinically accessible biomarkers to stratify disease severity or monitor treatment response. While NMDARs are well-studied in the central nervous system, they are also expressed in peripheral blood cells, including red blood cells (RBCs), where they modulate calcium signaling and cell function. Here we have used well-established in vivo and ex vivo methods to investigate hematological (primarily RBC-linked) phenotypes in transgenic mice carrying heterozygous Grin1 Y647S (Grin1^Y647S/+) variant. We found that Grin1^Y647S/+ mice had slightly increased RBC counts associated with increased erythropoiesis and normal erythropoietin levels. Functional assays revealed increased NMDAR-mediated calcium influx in Grin1^Y647S/+ RBCs, accompanied by reduced blood viscosity under flow conditions. Our findings provide the first genetic evidence that NMDAR gain-of-function leads to systemic changes in RBC physiology, which may contribute to core phenotypes of NMDAR-related disorders. Results point to several RBC indices that reflect altered NMDAR function in Grin1^Y647S/+ mice, providing foundational evidence for the development of peripheral blood biomarkers for patients with GRIN Disorder.