Grant: Project Grant

GRIN disorders are caused by mutations in the GRIN genes, which carry the instructions to make NMDA receptors. When children are born with these mutations, they have intellectual disability and often have other symptoms like movement disorders, loss of muscle tone, developmental delays, and seizures. Some patients are able to attend school, while others are non-verbal and must use a wheelchair. We want to understand the reasons why some patients have a milder phenotype than other patients. We also want to determine what the best treatment strategy should be. GRIN disorder is a new diagnosis that has only been made possible because of genome sequencing, and the long-term prognosis and best treatments are still not known. Therefore, we will use mouse models that harbor patient disease-causing mutations, and will study the phenotypes of these mice and test a number of therapeutic interventions. In Specific Aim 1, we study NMDA receptor biochemistry and function in model animals. In Specific Aim 2, we assess behavioural phenotypes to determine whether the severity of phenotypes parallels that of the patients. In Specific Aim 3, we test treatments for their ability to improve neurological impairments caused by mutations in GRIN genes.