Physiological mechanisms responsible for cognitive impairments in Dravet Syndrome

Dravet 综合征认知障碍的生理机制

• 批准号: 8611751
• 负责人: Pierre Pascal Lenck-Santini
• 金额: $ 33.03万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611751
• 关键词: ARHGEF5 gene; Action Potentials; Acute; Adult; Affect; Age; Alzheimer' s disease model; Antiepileptic Agents; Autistic Disorder; Behavioral; Cells; Child; Childhood; Cholinesterase Inhibitors; Code; Cognition; Cognitive; Data; Deterioration; Development; Disease; Down-Regulation; Electrophysiology (science); Epilepsy; Genes; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Injection of therapeutic agent; Interneurons; Intraventricular; Left; Link; Memory; Memory impairment; Modeling; Mutation; Neurons; Outcome; Patients; Performance; Pharmaceutical Preparations; Physiological; Play; Procedures; Process; Property; Pyramidal Cells; RNA Interference; Rattus; Role; SCN1A protein; Schedule; Seizures; Small Interfering RNA; Sodium Channel; Spatial Behavior; Structure; Syndrome; System; Techniques; Testing; Theta Rhythm; Time; Transfection; cognitive function; cognitive system; critical period; in vivo; information processing; loss of function mutation; nervous system disorder; neuromechanism; neuronal circuitry; relating to nervous system; research study; treatment strategy; voltage

Voltage gated Sodium channels (Nav) are critical for the initiation and propagation of action potentials. Mutations of the SCN1A gene, which codes for Nav type 1.1 cause Dravet Syndrome (DS), a severe childhood epileptic disorder associated with profound cognitive impairment. SCN1A mutations have also been described in autism and reduced levels of Nav1.1 are observed in various models of Alzheimer disease (AD). Nav1.1 is highly expressed in inhibitory interneurons that, as we defend here not only explains seizures but also cognitive impairments. Interneurons play a critical role in information processing by controlling the timing of action potentials and oscillatory activities. Alterations of such fundamental components of the neuronal circuitry are likely to have profound consequences on neural processing and, therefore cognition. The goal of this proposal is to investigate the physiological mechanisms leading to cognitive impairments and determine if there is a critical period of development where cognitive systems are permanently sensitive to the mutation effects. To approach this question, we have developed a technique to transiently suppress Nav1.1 expression using RNA interference in rats. This procedure induced cognitive impairments without seizures in rats and can be targeted at specific structures and initiated at specific developmental periods. We hypothesize that NaV1.1 deficits will be sufficient to affect neuronal coding, oscillatory activity and cognition. We also hypothesize that there is a critical period during which cognitive development is particularly sensitive to NaV1.1 abnormalities. To test these hypotheses, we will combine in vivo RNA interference, dynamic analysis of electro- encephalographic (EEG) oscillations and single cell electrophysiology (place cells) in rats performing memory tasks. The first part of this project will be to determine if there is a critical period during which NaV1.1 is critical for cognitive development. We will investigate the acute and long-term cognitive outcomes of intraventricular siRNA administration performed at different periods of post-natal development. In the second aim investigates the neural mechanisms by which NaV1.1 reduction induces cognitive impairments. Here, injections will be focused on a specific structure, the septo-hippocampal region, which is the neural substrate of spatial memory in rats. The role of interneurons in the physiological properties of this network is well characterized, making this an ideal network to investigate. The possibility that cognitive impairments may be caused by abnormal neuronal processing in addition to seizures would constitute a paradigm shift in the approach to DS and other childhood epilepsy disorders with poor cognitive outcome. It would suggest that additional treatment strategies focusing on cognitive function, other than traditional antiepileptic drugs may be necessary to recover normal cognitive function in affected children.

电压门控钠通道（NAV）对于动作电位的启动和传播至关重要。 SCN1A基因的突变，该基因编码为1.1型NAV导致Dravet综合征（DS），这是一个严重的童年 与深远的认知障碍有关的癫痫疾病。 SCN1A突变也已被描述 在自闭症和NAV1.1水平降低中，在各种阿尔茨海默氏病（AD）中观察到。 NAV1.1是 在抑制性中间神经元中高度表达，正如我们在这里辩护的那样，不仅解释了癫痫发作，而且还解释 认知障碍。中间神经元通过控制信息处理在信息处理中起关键作用 动作潜力和振荡活动。神经元电路的这种基本组成部分的改变 可能会对神经加工和认知产生深远的影响。 该提案的目的是研究导致认知障碍和的生理机制 确定认知系统永久敏感的发展是否存在关键时期 突变效应。为了解决这个问题，我们已经开发了一种技术来瞬时抑制NAV1.1 在大鼠中使用RNA干扰的表达。该程序引起的认知障碍而没有癫痫发作 大鼠可以针对特定的结构，并在特定的发育期开始。我们假设 NAV1.1缺陷足以影响神经元编码，振荡活性和认知。我们 还假设存在一个关键时期，在此期间，认知发展尤其是 对NAV1.1异常敏感。 为了检验这些假设，我们将结合体内RNA干扰，电动分析 脑电图（EEG）振荡和单细胞电生理学（位置细胞）的大鼠进行记忆 任务。该项目的第一部分将是确定NAV1.1至关重要的关键时期是否存在关键时期 用于认知发展。我们将研究脑室室内的急性和长期认知结果 siRNA给药在产后发育的不同时期进行。在第二个目标中调查 NAV1.1减少诱导认知障碍的神经机制。在这里，注射将是 侧重于特定结构，即隔海马区域，该区域是空间记忆的神经底物 在老鼠中。中间神经元在该网络的生理特性中的作用已经很好地表征 一个理想的研究网络。 认知障碍可能是由异常神经元处理引起的可能性 癫痫发作将构成DS和其他儿童癫痫疾病的方法的范式转变 认知结果不佳。这表明其他重点是认知功能的治疗策略， 除了传统的抗癫痫药物以外，可能需要恢复受影响的正常认知功能 孩子们。