Mechanisms of GRIN2D Developmental Delay and Epilepsy

Genetic mutations in the GRINZD gene cause severe epilepsy with intellectual disability and motor problems. Although the genetic causes of the disease are known, there are no effective treatment options. Moreover, we are yet to understand why these genetic changes lead to the severe neurological phenotypes. Here, we propose to study a novel mouse model, that recapitulate the human disease, based on the recurrent GRIN2D Val667lle mutation. Importantly, our preliminary data already demonstrate that these mice faithfully mimic the core phenotypes of GRIN2D patients, with frequent and prolonged epileptic seizures and altered motor function. Here we propose to further characterize the development and motor abilities of these mice. Moreover, by performing recordings of brain activity, from the cellular to the whole animal levels, we will unveil the functional changes that lead to altered brain activity. Furthermore, this model will serve to explore the therapeutic potential of different groups of drugs, including established anti-epileptic agents, and additional drugs as indicated by our functional data. Last, we will compare the therapeutic effects following acute and chronic treatment regimens. Together, this study will unveil the hidden connections between GRINZD genetic mutation and the resultant neurodevelopmental disease and will provide a firm steppingstone for the development of novel and effective treatment for this intractable disease.