Cortical development and pathogenesis in DEPDC5-related epilepsies

摘要 局灶性皮质发育不良(FCD)是耐药儿童最常见的潜在病理 癫痫。DEPDC5突变已被越来越多地认为是糖尿病最重要的遗传原因 伴或不伴FCD的局灶性癫痫。使用焦点体细胞突变方法，我们最近产生了一种 具有与人类FCD高度临床相关的病理和电信号特征的啮齿动物模型。 然而，Depdc5突变是如何引起发育不良的皮质和癫痫的确切原因仍不清楚。我们 建议将重点放在定义潜在的遗传、细胞和回路机制 研究DEPDC5相关的癫痫，以及确定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 发育和癫痫。我们的中心假设是，皮质祖细胞中的DEPDC5突变会产生 局灶性内源性癫痫通过其在塑造神经和神经胶质发育中的关键作用，以及 抑制mTORC1募集将恢复细胞结构，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.