A Comparative Study Of Sudden Unexpected Death In Mouse Models Of Focal Cortical Dysplasia And Dravet Syndrome
Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in people with treatment-resistant epilepsies. But, its mechanisms are not completely understood. Such life-threatening epilepsies include epilepsy associated with Focal Cortical Dysplasia (FCD) and Dravet syndrome (DS). FCD is developmental disorder marked by abnormal formation of the cerebral cortex. It has been recently associated with mutations in PIK3CA gene. DS is a severe pediatric epilepsy, with one of the highest rates of SUDEP. DS is caused by mutations in SCN1A gene. In recent studies, we found that SUDEP of our mouse model of DS occurs when a severe seizure causes hyperactivity of the vagus nerve, which is immediately followed by prolonged bradycardia and ventricular dysfunction. In the studies proposed in this research project, we will use our DS mouse model and a recent mouse model of FCD to examine whether there is a common mechanism of sudden unexpected death in these two types of epilepsy. We will conduct experiments to Identify and compare the cardiac, respiratory, and post-seizure brain activity changes that predict SUDEP susceptibility in DS and FCD mice. In addition, we will characterize and compare the neuronal circuits that mediates these SUDEP-related physiological anomalies.