DECODING THE CELLULAR AND MOLECULAR MECHANISMS OF EPILEPTOGENESIS AND DISEASE PROGRESSION IN MTOROPATHIES - ABSTRACT MTOROPATHIES, SUCH AS FOCAL CORTICAL DYSPLASIA TYPE II (FCDII), IS THE MOST COMMON UNDERLYING PATHOLOGY IN CHILDREN WITH DRUG-RESISTANT EPILEPSIES. HOWEVER, THE UNDERLYING MECHANISMS OF EPILEPTOGENESIS, HYPEREXCITABILITY, AND DISEASE PROGRESSION REMAIN LARGELY ELUSIVE. IN THIS PROPOSAL, WE COMBINE ANIMAL MODELS AND RESECTED HUMAN TISSUES TO UNDERSTAND THE CELLULAR AND MOLECULAR LOGIC NETWORKS IN THE DYSPLASTIC CORTEX. WE USE CUTTING-EDGE TECHNOLOGIES IN MOLECULAR GENETICS, ELECTROPHYSIOLOGY, TRANSGENICS, AND RNA SEQUENCING TO PROVIDE CONCEPTUAL INSIGHTS BROADLY RELEVANT TO UNDERSTANDING MTOR-RELATED EPILEPSIES. OUR CENTRAL HYPOTHESIS IS THAT A SUSTAINED NEUROTOXIC MICROENVIRONMENT MEDIATED BY COMPLEMENT COMPONENT C3 PROGRESSIVELY SCULPTS CELLULAR AND MOLECULAR ARCHITECTURES, IMPAIR CORTICAL INHIBITORY CIRCUITS, AND PROMOTE EPILEPTOGENICITY IN THE MALFORMED CORTEX.