Grant: Operating Grant: ECI grants in Maternal, Reproductive, Child & Youth Health

Epilepsy affects about 1 in 200 children and adolescents in Canada. Treatment of epilepsy presents a complex challenge because it is caused by vastly different mechanisms that perturb the brain circuitry. As a result, 30%-40% of epilepsy patients do not respond to drug treatments. Children and youth with uncontrollable epilepsy are not only at a higher risk of mortality but also more likely to have learning disabilities, depression, and anxiety, leading to reduction in quality of life. Further insight into the etiology of treatment-resistant epilepsy is needed to develop effective therapies for children and youth suffering from this devastating neurological condition. An abnormally large number of Cajal-Retzius cells-a type nerve cells that are mostly found in the brain during embryonic development-have been reported in cut-out brain tissues from patients undergoing epilepsy surgery. This suggests a role of Cajal-Retzius cells in difficult-to-treat epilepsy. But how Cajal-Retzius cells constitute an important element in the pathogenic cascade of epilepsy is unknown. Addressing this question has proven challenging, partly due to the lack of animal models that mimic the human pathology of abnormal Cajal-Retzius cell persistence. Here, we have developed a unique mouse model with an abnormally high number of Cajal-Retzius cells. Armed with this mouse model, we ask: 1)What causes Cajal-Retzius cell to abnormally persist in the postnatal/juvenile brain? 2)How does abnormal Cajal-Retzius cell persistence contribute to seizure susceptibility? We design a set of experiments to investigate how Cajal-Retzius cell death is regulated. We will determine whether abnormal Cajal-Retzius cell persistence, and therefore their abnormal activity, contributes to increased seizure susceptibility.