Mouse Models of GRIN1-Related Neurodevelopmental Disorder and Initial Investigations of Endocannabinoid Modulating Treatments

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors formed as tetrameric complexes of two GluN1 subunits plus two copies of GluN2 or GluN3 subunits, or a mixture of both. These receptors mediate excitatory neurotransmission and play critical roles in processes underlying development, learning and memory. GRIN1-Related Neurodevelopmental Disorder (GRIN1-NDD), is characterized by clinically significant variation in the GRIN1 gene, which encodes the obligatory GluN1 subunit of NMDARs. Patients present with a wide range of symptoms of varying severity but nearly all display developmental delay and intellectual disability, while some patients present with epilepsy which is refractory to treatment. The diversity of phenotypes observed across GRIN1-NDD has been attributed, in part, to the multitude of unique GRIN1 variants identified in patients. Here, we examine the p.Tyr647Ser variant carried by a 34-year-old female and the p.Gln536Arg carried by a 17-year-old male patient. In vitro methods have revealed these variants distinctly alter NMDAR function, however, the impact of these alterations remain unstudied in whole organism systems, which is critical to comprehensively understanding mechanisms underlying GRIN1-NDD and identifying novel treatments. To address this, the present study characterized Grin1Y647S/+ and Grin1Q536R/+ mouse models that harbour mutations orthologous to those identified in patients. Molecular, histological and behavioural methods were utilized to provide initial investigations into in vivo pathological mechanisms, to identify phenotypes in domains relevant to GRIN1-NDD symptomology and to test potential treatments which modulate the endocannabinoid system. Additionally, de-identified patient data was collected to examine the representative nature of these mice in modelling specific aspects of patient symptomology. Grin1Y647S/+ and Grin1Q536R/+ displayed alterations to GluN1 subunits levels and motor, social, cognitive and seizure phenotypes relevant to GRIN1-NDD symptomology and reminiscent of patient clinical severity in each case. In particular, Grin1Y647S/+ mice displayed robust spontaneous seizures and locomotor phenotypes, which were utilized to identify novel treatments, such as JZL-184, an inhibitor of endocannabinoid metabolism. Overall, the characterization of Grin1Y647S/+ and Grin1Q536R/+ mouse models accomplished in the present study, is a foundational step towards expanding our understanding of mechanisms underlying GRIN1-NDD and developing novel therapeutics to better meet the needs of patients.

Department dc:contributor.department

Pharmacology

Year dc:date.issued

2025

Author dc:creator

• Sullivan, Megan Taylor

Advisor dc:contributor.advisor

• Ramsey, Amy J

• Endocannabinoid System
• Mouse Model
• Neurodevelopmental Disorder
• NMDA Receptor

Handle dc:identifier.uri

https://hdl.handle.net/1807/150010

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/150010