Developmental Pathophysiology in Neocortex Caused By Somatic Mutations

每一个细胞都有一个独特的突变组合，这些突变是由不完美的细胞积累起来的。 DNA修复如果这些体细胞突变发生在大脑皮层的关键早期， 它们可以影响大脑中足够的细胞，损害功能， 病理生理学也许体细胞突变导致 人类大脑中的病理生理学是由神经胶质和神经胶质-神经元肿瘤引起的癫痫发作， 大脑皮层发育不良迄今为止在这些疾病中发现的最常见的体细胞突变是 病变包括在大约30-50%的切除的 神经节细胞胶质瘤和局灶性皮质中MTOR、AKT和PIK 3CA激酶的激活突变 发育不良目前的证据表明，这些突变是潜在的 导致局灶性癫痫的病理学这与病灶性躯体疾病 最近的研究表明，神经元和/或神经胶质细胞亚群的突变足以引起癫痫发作， 已经表明，在切除的人体组织中鉴定的突变的表达相对较小， 小鼠皮层神经元的数量足以引起癫痫发作。在很大程度上， 目前还不清楚不同的体细胞突变是如何以及是否会导致神经元的 皮质神经元的过度兴奋和皮质回路的超同步。使用新型动物 模型的局灶性体细胞突变的神经祖细胞，我们提出测试三个假设 重点是确定癫痫发作的潜在发育，细胞和分子原因 由皮质的体细胞突变引起：1）细胞表型和癫痫发作的严重程度是一个 新皮质祖细胞的功能，其中癫痫发生突变，2） 皮质兴奋性升高是MAPK/ERK和MTOR过度活跃的直接结果 神经元和星形胶质细胞之一或两者中的通路，以及3）癫痫样活动扩散 通过改变与抑制性中间神经元网络的连接， 导致超同步的中间神经元活动。

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.