Neurophysiological mechanisms of cognitive impairment in Severe Myoclonic Epileps

重症肌阵挛性癫痫认知障碍的神经生理机制

基本信息

批准号：
8516126
负责人：
Alex Colbath Bender
金额：
$ 3.88万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516126
关键词：
Absence Epilepsy Action Potentials Address Adult Affect Animal Model Antiepileptic Agents Area Behavioral Benchmarking Biological Biological Neural Networks Brain Cells Childhood Code Cognition Cognitive Cognitive deficits Comorbidity Development Disease Dorsal Electroencephalography Epilepsy Equilibrium Frequencies Future Gene Mutation Genes Genetic Goals Hippocampus (Brain)Impact Seizures Impaired cognition Impairment Implanted Electrodes Individual Interneuron function Interneurons Investigation Learning Life Medial Mediating Memory Monitor Mutation Myoclonic Epilepsies National Institute of Neurological Disorders and Stroke Outcome Parvalbumins Patients Pattern Performance Pharmaceutical Preparations Phase Physiology Play Population Process Prosencephalon Pyramidal Cells RNA Interference Rattus Research Research Project Grants Role Seizures Small Interfering RNA Sodium Channel Structure Subgroup Syndrome System Techniques Testing United States National Institutes of Health base cell type cognitive function gene function human TFRC protein improved in vivo infancy information processing loss of function mutation neurophysiology novel strategies prevent research study septohippocampal spatiotemporal therapy development tool treatment strategy voltage young adult

项目摘要

Severe Myoclonic Epilepsy in Infancy (SMEI), also referred to as Dravet syndrome, is a childhood disorder associated with loss-of-function mutations in Scn1a that is characterized by frequent seizures and severe cognitive impairment. Patients are often intractable to anti-epileptic drugs and do not recover normal cognitive function later in life. In order to determine appropriate treatment strategies for improving cognitive outcomes, it is first necessary to understand the underlying biological contributions to cognitive dysfunction. Although the cognitive deficits in epilepsy are often attributed to the impact of seizures, we propose that the genetic deficit associated with SMEI leads to neurophysiological alterations in brain network activity and contributes to cognitive impairment independently of seizures. This possibility may hold important implications for investigating future treatments aimed to improve cognition. It would suggest that cognitive function may not fully recover by treating seizures alone. This investigation will therefore be important to determine if additional treatment strategies to the traditional anti-epileptic drugs should be pursued in the effort to develop therapies for improving cognitive outcome. The Scn1a gene encodes for the type I voltage-gated sodium channel. In the forebrain, Scn1a deficits cause impaired action potential firing of parvalbumin-positive (PV+) interneurons but not excitatory pyramidal cells. In addition to the contribution of this cell type to balancing excitation and inhibition in the brain, PV+ interneurons play critical roles in the spatiotemporal patterning of neural networks, especially during cognitive processes. In the septo-hippocampal system, these cells are required for brain network oscillations and temporal coding, and selective impairments in this interneuron population result in impaired cognitive performance on learning and memory tasks. Therefore, the septo-hippocampal system may be one network affected by Scn1a deficits. The goal of this proposal is to address the question of whether Scn1a deficits contribute to cognitive impairment. We hypothesize that Scn1a deficits in the septo-hippocampal system are sufficient to impair cognition independently of the seizure disorder. We will use in vivo electrophysiological and behavioral techniques combined with RNAi silencing of Scn1a expression in rats to test this hypothesis. Our specific aims are to (1) determine the effects of Scn1a deficits in the septo-hippocampal system on cognition, and (2) to investigate the effects of Scn1a deficits on neural network oscillations and coding. These experiments will be important for elucidating a neural network mechanism that may contribute to impaired cognition caused by Scn1a gene mutations.

婴儿期严重的肌阵挛性癫痫（SMEI），也称为Dravet综合征，是一种与SCN1A功能丧失突变有关的儿童疾病，其特征是频繁癫痫发作和严重的认知障碍。患者通常对抗癫痫药很棘手，并且在以后的生活中不会恢复正常的认知功能。为了确定改善认知结果的适当治疗策略，首先需要了解对认知功能障碍的基本生物学贡献。尽管癫痫的认知缺陷通常归因于癫痫发作的影响，但我们建议与SMEI相关的遗传缺陷会导致脑网络活动的神经生理变化，并独立于癫痫发作有助于认知障碍。这种可能性可能对调查旨在改善认知的未来治疗具有重要意义。这表明认知功能可能不会单独治疗癫痫发作来完全恢复。因此，这项调查对于确定是否应采用传统抗癫痫药物的其他治疗策略来开发改善认知结果的疗法，这将很重要。 SCN1A基因编码I型电压门控钠通道。在前脑中，SCN1A缺陷会导致类动作阳性（PV+）中间神经元的动作电势发射，而不是兴奋性锥体细胞。除了这种细胞类型对平衡大脑的激发和抑制的贡献外，PV+中间神经元在神经网络的时空图案中起着关键作用，尤其是在认知过程中。在九月 - 海马系统中，这些细胞是大脑网络振荡和时间编码所必需的，并且该间神经元种群中的选择性损害会导致学习和记忆任务的认知性能受损。因此，隔s-Hampocampal系统可能是一个受SCN1A缺陷影响的网络。该提案的目的是解决SCN1A缺陷是否有助于认知障碍的问题。我们假设SEPTO-HAPPOCAMPAL系统中的SCN1A缺陷足以独立于癫痫发作障碍而损害认知。我们将使用体内电生理和行为技术结合大鼠中SCN1A表达的RNAi沉默来检验该假设。我们的具体目的是（1）确定septo-Hampocampal系统中SCN1A缺陷对认知的影响，以及（2）研究SCN1A缺陷对神经网络振荡和编码的影响。这些实验对于阐明可能导致SCN1A基因突变引起的认知受损的神经网络机制至关重要。