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.

癫痫是一种涉及远远超过癫痫发作的疾病，癫痫发作可引起神经元网络紊乱，导致广泛的认知和行为障碍。迄今为止，癫痫领域的大多数工作都集中在发作事件本身的机制或预防上。我的实验室的重点一直是对大脑发育和癫痫发生的早期生命癫痫发作的影响。目前的建议扩展了我们的工作，以确定这些机制是否也会引起可能导致早期生活中表现出认知功能障碍的改变，如自闭症。有临床证据表明，生命早期癫痫发作可能是自闭症的许多先例之一，而癫痫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，基线突触可塑性增强，癫痫发作似乎直接激活特定的可塑性相关的信号通路。我们假设癫痫是诱发的？发育不良？可能会阻塞与认知有关的正常可塑性，并诱导突触发育的异常模式，类似于在自闭症和其他形式的神经发育迟缓中观察到的模式。利用电生理学技术，我们将首先研究在未成熟的大脑中，电刺激引起的正常突触可塑性中断的时间过程。然后，我们将确定是否特定的活动依赖性信号异常已知与自闭症发生从头癫痫发作后，在未成熟的大脑。接下来，我们将确定癫痫发作诱导的机制，他们的激活和测试是否癫痫发作后干预减弱神经元网络的结构和功能的改变。最后，我们将确定是否在癫痫发作后的人体组织中以及在与新生儿或婴儿癫痫发作相关的自闭症病例中也观察到信号传导、调节和突触蛋白的类似改变。