GRIN1, encoding the obligatory GluN1 subunit of N-methyl-D-aspartate receptors (NMDARs), is crucial for synaptic transmission, plasticity, and neural circuit development. NMDARs are a subtype of ionotropic glutamate receptors, and their proper function is essential for normal brain development and cognitive function [1,3].

In KO/CKO mouse models, disruption of Grin1 within corticotropin-releasing factor (CRF) neurons enhanced fear memory, suggesting its role in fear-related behaviors [5]. Grin1 loss-of-function mutations in male Grin1-/-knockdown mice led to volume reductions in dopaminergic structures early in development, with delayed changes in limbic and white matter structures, indicating its importance in maintaining normal brain structure [6]. The Grin1 Y647S/+ mouse model, created by CRISPR-Cas9, displayed reduced whole-brain GluN1 levels, deficient NMDAR-mediated synaptic transmission in the hippocampus, and exhibited spontaneous seizures, altered vocalizations, muscle strength, sociability, and problem-solving, mimicking some clinical features of GRIN1-related neurodevelopmental disorder [8].

In conclusion, GRIN1 is essential for normal brain function, including synaptic transmission, neural circuit development, and the regulation of fear-related behaviors. Mouse models with Grin1 gene knockout or conditional knockout have provided valuable insights into its role in neurodevelopmental disorders, such as epileptic encephalopathy, intellectual disability, and autism, by revealing the impact of its loss-of-function on brain structure and function [2,3,4,6,7,8].

References:

1. Korinek, M, Candelas Serra, M, Abdel Rahman, Fes, Balik, A, Smejkalova, T. 2024. Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology. In Physiological research, 73, S413-S434. doi:. https://pubmed.ncbi.nlm.nih.gov/38836461/

2. Blakes, Alexander J M, English, Joel, Banka, Siddharth, Basu, Helen. 2021. A homozygous GRIN1 null variant causes a more severe phenotype of early infantile epileptic encephalopathy. In American journal of medical genetics. Part A, 188, 595-599. doi:10.1002/ajmg.a.62528. https://pubmed.ncbi.nlm.nih.gov/34611970/

3. Ragnarsson, Lotten, Zhang, Zihan, Das, Sooraj S, Vetter, Irina, Keramidas, Angelo. 2023. GRIN1 variants associated with neurodevelopmental disorders reveal channel gating pathomechanisms. In Epilepsia, 64, 3377-3388. doi:10.1111/epi.17776. https://pubmed.ncbi.nlm.nih.gov/37734923/

4. Allen, Andrew S, Berkovic, Samuel F, Cossette, Patrick, Widdess-Walsh, Peter, Winawer, Melodie R. 2013. De novo mutations in epileptic encephalopathies. In Nature, 501, 217-21. doi:10.1038/nature12439. https://pubmed.ncbi.nlm.nih.gov/23934111/

5. Gafford, Georgette, Jasnow, Aaron M, Ressler, Kerry J. 2014. Grin1 receptor deletion within CRF neurons enhances fear memory. In PloS one, 9, e111009. doi:10.1371/journal.pone.0111009. https://pubmed.ncbi.nlm.nih.gov/25340785/

6. Intson, Katheron, van Eede, Matthijs C, Islam, Rehnuma, Henkelman, R Mark, Ramsey, Amy J. 2019. Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation. In Neurobiology of disease, 132, 104527. doi:10.1016/j.nbd.2019.104527. https://pubmed.ncbi.nlm.nih.gov/31299220/

7. Brock, Stefanie, Laquerriere, Annie, Marguet, Florent, Fry, Andrew E, Bahi-Buisson, Nadia. 2022. Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B. In Journal of medical genetics, 60, 183-192. doi:10.1136/jmedgenet-2021-107971. https://pubmed.ncbi.nlm.nih.gov/35393335/

8. Sullivan, Megan T, Tidball, Patrick, Yan, Yuanye, Collingridge, Graham L, Ramsey, Amy J. 2024. Grin1 Y 647 S/+ Mice: A Preclinical Model of GRIN1 -Related Neurodevelopmental Disorder. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.08.21.608984. https://pubmed.ncbi.nlm.nih.gov/39229143/