Understanding the Cognitive Impact of Early Life Epilepsy

了解早期癫痫对认知的影响

• 批准号: 7681264
• 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/7681264
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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.

癫痫是一种不仅仅涉及癫痫发作的疾病，而且 癫痫发作可引起神经网络紊乱，从而导致多种症状 认知和行为障碍。迄今为止，癫痫领域的大部分工作 集中于发作事件本身的机制或预防。重点是 我的实验室一直在研究生命早期癫痫发作对大脑发育的影响 癫痫发生。目前的提案扩展了我们的工作，以确定这些是否 机制也会引起可能导致认知功能障碍的改变 在生命早期，例如自闭症。有临床证据表明早期癫痫发作可能是其中之一 自闭症的先例很多，而癫痫在自闭症患者中很常见， 表明两个过程之间存在相互作用。我们之前和最近的工作 表明至少在未成熟的大脑中，基线突触可塑性是 增强的癫痫发作似乎直接激活特定的可塑性相关信号 途径。我们假设癫痫引起的发育不良可能会遮挡正常的 参与认知的可塑性，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迟缓中观察到的情况。使用 电生理技术，我们首先检查癫痫发作的时间过程 未成熟大脑中正常突触可塑性的中断。然后我们将确定 是否已知与特定活性依赖性信号异常相关 自闭症是在未成熟的大脑癫痫发作后重新发生的。接下来我们将识别 癫痫发作诱导机制的激活并测试癫痫发作后是否 干预会减弱神经网络结构和功能的改变。最后， 我们将确定信号、调节和突触方面是否存在类似的改变 癫痫发作后和自闭症患者的人体组织中也观察到了蛋白质 与新生儿或婴儿癫痫发作有关。