Understanding the Cognitive Impact of Early Life Epilepsy

了解早期癫痫对认知的影响

• 批准号: 7341202
• 负责人: Frances E Jensen
• 金额: $ 84.5万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341202
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Epilepsy is a disorder that involves far more than the occurrence of seizures, and seizures can cause neuronal network disturbances that result in a wide range of cognitive and behavioral impairment. To date, most work in the epilepsy field has centered on the mechanism or prevention of the ictal events themselves. The focus of my laboratory has been on the impact of early life seizures on brain development and epileptogenesis. The present proposal extends our work to determine whether these mechanisms also induce alterations that could lead to cognitive dysfunction manifesting in early life, such as autism. There is clinical evidence that early life seizures may be one of many precedents for autism, and epilepsy is common in patients with autism, suggesting an interaction between the two processes. Our prior and recent work suggests that at least in the immature brain, where baseline synaptic plasticity is enhanced, seizures appear to directly activate specific plasticity-associated signaling pathways. We hypothesize that seizure induced ?dysplasticity? may occlude normal plasticity involved in cognition, and induce abnormal patterns of synapse development similar to those observed in autism and other forms of neurodevelopmental delay. Using electrophysiological techniques, we will first examine the time course of seizure-induced interruption of normal synaptic plasticity in the immature brain. We will then determine whether specific activity-dependent signaling abnormalities known to be associated with autism occur de novo following seizures in the immature brain. Next, we will identify seizure induced mechanisms for their activation and test whether post-seizure intervention attenuates the altered structure and function of neuronal networks. Finally, we will determine whether similar alterations in signaling, regulatory, and synaptic proteins also are observed in human tissue following seizures and in cases of autism associated with neonatal or infantile seizures.

癫痫病是一种涉及的疾病，远远超过癫痫发作的发生，癫痫发作会导致神经元网络扰动，从而导致广泛的认知和行为障碍。迄今为止，癫痫领域中的大多数工作都集中在发行事件本身的机制或预防上。我的实验室的重点一直是早期癫痫发作对脑发育和癫痫发生的影响。本提案扩展了我们的工作，以确定这些机制是否也引起可能导致早期生活（例如自闭症）表现出认知功能障碍的改变。有临床证据表明，早期癫痫发作可能是自闭症的众多先例之一，癫痫病在自闭症患者中很常见，这表明这两个过程之间存在相互作用。我们的先前和最近的工作表明，至少在未成熟的大脑中，基线突触可塑性得到增强，癫痫发作似乎直接激活了特定的可塑性相关信号通路。我们假设癫痫发作的癫痫发作？可能会阻止与认知有关的正常可塑性，并诱导突触发育的异常模式，类似于自闭症和其他形式的神经发育延迟中的异常。使用电生理技术，我们将首先检查癫痫发作诱导的未成熟大脑正常突触可塑性中断的时间过程。然后，我们将确定在未成熟大脑中癫痫发作后，已知与自闭症相关的特定活性依赖性信号传导异常是否从头出现。接下来，我们将确定癫痫发作的激活机制，并测试癫痫后干预是否会减弱神经元网络的结构和功能的改变。最后，我们将确定在癫痫发作后以及与新生儿或婴儿癫痫发作有关的自闭症的情况下，在人体组织中也观察到信号传导，调节和突触蛋白的类似变化。