Cortical development and pathogenesis in DEPDC5-related epilepsies

摘要 局灶性皮质发育不良（FCD）是耐药儿童中最常见的潜在病理学， 癫痫DEPDC5突变已越来越被认为是最重要的遗传原因， 局灶性癫痫伴或不伴FCD。使用焦点体细胞诱变方法，我们最近产生了一个 啮齿类动物模型的病理学和电图特征与人类FCD高度临床相关。 然而，究竟发育不良的皮质和癫痫发作是如何由Depdc 5突变引起的仍然未知。我们 我建议把重点放在定义潜在的遗传，细胞和电路机制，有助于 DEPDC5相关癫痫以及建立DEPDC5在皮质发育中的关键作用。我们 将提供与理解mTOR相关的皮质畸形广泛相关的概念性见解， 发展和癫痫。我们的中心假设是，皮质祖细胞中的DEPDC 5突变产生 通过其在塑造神经和神经胶质发育中的关键作用， 抑制mTORC 1募集将恢复细胞结构并抑制癫痫发作。

ABSTRACT Focal cortical dysplasia (FCD) is the most common underlying pathology in children with drug resistant epilepsies. DEPDC5 mutations have been increasingly recognized as the most important genetic cause in focal epilepsies with or without FCD. Using focal somatic mutagenesis approaches, we recently generated a rodent model with pathological and electrographic signatures that are highly clinically-relevant to human FCD. However, precisely how dysplastic cortex and seizures arise from Depdc5 mutation remains unknown. We propose to focus on defining the underlying genetic, cellular and circuitry mechanisms contributing to DEPDC5-related epilepsies as well as establishing the critical roles of DEPDC5 in cortical development. We will provide conceptual insights broadly relevant to understanding mTOR-related malformation of cortical development and epilepsies. Our central hypothesis is that DEPDC5 mutations in cortical progenitors generate focal intrinsic epileptogenecity through its critical roles in sculpting neural and glial development, and that inhibition of mTORC1 recruitment will restore cytoarchitectures and suppress seizures.