Developmental Pathophysiology in Neocortex Caused By Somatic Mutations

每个细胞都有独特的突变组合，这些突变是由不完美积累而成的

Every cell has a unique combination of mutations that have accumulated by imperfect DNA repair. If these somatic mutations occur in a critical early time in cerebral cortical development they can affect enough cells in the brain to impair function and result in pathophysiology. Perhaps the best demonstrated examples of somatic mutations causing pathophysiology in the human brain are seizures caused by glial and glial-neuronal tumors and by focal cortical dysplasias. The most common somatic mutations identified to date in these lesions include activating BRAF kinase mutations in approximately 30-50% of resected gangliogliomas, and activating mutations in MTOR, AKT, and PIK3CA kinases in focal cortical dysplasias. Current evidence suggests that these mutations are drivers of the underlying pathologies responsible for focal epilepsies. Consistent with the idea that focal somatic mutations in a subset of neurons and/or glia are sufficient to cause seizures, recent studies have shown that expression of mutations identified in resected human tissue in relatively small numbers of cortical neurons in mice is sufficient to cause seizures. What remains largely unknown is precisely how and whether different somatic mutations lead to neuronal hyperexcitability in cortical neurons and hypersynchrony in cortical circuits. Using novel animal models of focal somatic mutation in neural progenitors we propose to test three hypotheses focused on defining the underlying developmental, cellular and molecular causes of seizures resulting from somatic mutations in cortex: 1) cellular phenotypes and seizure severity are a function of the neocortical progenitors in which epileptogenic mutations arise, 2) elevated cortical excitability is a direct consequence of overactive MAPK/ERK and MTOR pathways in either or both neurons and astrocytes, and 3) epileptiform activity spreads from perilesional zones by altered connections to inhibitory interneuron networks that result in hypersynchronous interneuron activity.