Adhesion molecules and developmental epilepsy disorders

项目摘要 这是一份旨在了解大脑异常发育和功能的赠款的更新申请， 与癫痫共病的神经发育障碍，并探索潜在的临床前挽救策略 来逆转这些异常。神经发育障碍，如智力残疾和自闭症， 与癫痫发作障碍共病，如癫痫。最近发现了一些基因的突变 其引起与癫痫共病的神经发育障碍，提示共同的病因机制。 在这些基因中，编码神经元粘附分子的基因是非常高度代表的。在此，我们建议 继续研究这个家族的一个突出代表CNTNAP 2突变的新的神经元功能， 其引起智力残疾、孤独症和语言障碍的单基因综合征，与癫痫共病。 具体地说，我们将研究CNTNAP 2胞外域脱落（切割和细胞分裂）的神经发育功能。 细胞外结构域的释放）。根据我们上一个资助期的调查结果， 我们假设CNTNAP 2胞外域的特定区域可以调节网络特性和癫痫发作， 在完整小鼠脑中的活性; CNTNAP 2-ecto脱落在具有和小鼠模型的人类受试者中失调 神经发育性癫痫我们将结合分子生物学的专业知识来验证这一假设。 神经生物学、癫痫、蛋白质组学和药理学，使用动物模型和人类临床CSF样本，以及 通过采用几种先进的方法，在以下具体目标：1）映射结构 CNTNAP 2-ecto功能的决定因素。2)描述CNTNAP 2-ecto对网络和癫痫发作的影响 在小鼠中的活动。3)探讨脑脊液中检测到的脱落胞外域与癫痫发作活动的关系。 在基本的层面上，产生的数据将提供新的见解旁分泌信号的生物学神经元 细胞外结构域脱落和揭示新的机制，调节神经元网络活动在大脑发育。 从长远来看，我们的研究将提供新的见解的分子基础上的变化，在癫痫和 神经发育障碍，并有可能提供临床前的原则证明，为新的治疗 发展性癫痫发作障碍的干预策略。

PROJECT SUMMARY This is a renewal application for a grant aimed to understand abnormal brain development and function in neurodevelopmental disorders co-morbid with epilepsy, and to explore preclinical rescue strategies with the potential of to reverse these abnormalities. Neurodevelopmental disorders, such as intellectual disability and autism are often comorbid with seizure disorders, such as epilepsy. Mutations in a number of genes have recently been discovered which cause neurodevelopmental disorders comorbid with epilepsy, suggesting common etiological mechanisms. Among these, genes encoding neuronal adhesion molecules are very highly represented. Here we propose to continue to investigate novel neuronal functions of a prominent representative of this family, CNTNAP2, mutations in which cause monogenic syndromes of intellectual disability, autism, and language disorder, comorbid with epilepsy. Specifically, we will investigate the neurodevelopmental functions of CNTNAP2 ectodomain shedding (cleavage and release of the extracellular domain) in paracrine signaling. Based on our findings from the previous funding period, we hypothesize that specific regions on CNTNAP2's ectodomain can modulate network properties and seizure activity in the intact mouse brain; CNTNAP2-ecto shedding is dysregulated in human subjects with and mouse models of neurodevelopmental seizure disorders. We will test this hypothesis by combining expertise in molecular neurobiology, epilepsy, proteomics, and pharmacology, using animal models and human clinical CSF samples, and by employing several cutting-edge methodologies, in the following Specific Aims: 1) To map the structural determinants of CNTNAP2-ecto function. 2) To characterize the impact of CNTNAP2-ecto on network and seizure activity in mice. 3) To explore the relationship between shed ectodomains detected in the CSF and seizure activity. On a basic level, data generated will provide new insights into the biology of paracrine signaling by neuronal ectodomain shedding and reveal novel mechanisms of regulation neuronal network activity during brain development. In the long run, our studies will provide novel insight into the molecular basis of alterations in both epilepsy and neurodevelopmental disorders and have the potential to provide preclinical proof-of-principle for novel therapeutic strategies for interventions in developmental seizure disorders.