Malformation of cortical development (MCD) are a common cause of epilepsy, which underscores molecular and genetic networks shared by developmental defects in neocortex and epilepsy. Studies in the largest epilepsy surgery series show that MCD is the most common pathology in children with medically refractory epilepsies. However, the basic mechanism underlying the epileptogenesis in MCD is poorly understood. For this MCubed project, we propose to define the genetic, cellular and circuit mechanisms that underlie epilepsies in MCD, which will provide insights into the relationship between epileptogensis and cortical development. The team members have complementary expertise to tackle this problem. Dr. Wang is a neurologist and neuroscientist with expertise in neurodevelopmental disorders, in particular, epilepsy. His lab has expertise in genome editing methods, in utero electroporation, EEG monitoring and analysis, and in vivo electrophysiology recordings. Dr. Kwan is an expert on genetic mechanisms of cortical development. His lab has a strong record of mechanistic dissection of neurodevelopment and expertise on genetics, genomics, and brain somatic mosaicism. Dr. Ye is an expert on molecular mechanisms that underlie neurodevelopment and neurodevelopmental disorders. His lab has recently identified molecular mechanisms that underlie the morphogenesis and synaptogenesis of GABAergic neurons in neocortex, which is a major player in epileptogenesis. Successful completion of the MCubed project will yield mechanistic and clinically relevant understanding of how genetic mutations generate epileptogenic lesions at genetic, cellular and circuitry levels.