Physiological mechanisms responsible for cognitive impairments in Dravet Syndrome

Dravet 综合征认知障碍的生理机制

基本信息

批准号：
8740093
负责人：
Pierre Pascal Lenck-Santini
金额：
$ 15.66万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
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/8740093
关键词：
ARHGEF5 gene Action Potentials Acute Adult Affect Age Antiepileptic Agents Behavioral Cells Child Childhood Code Cognition Cognitive Data Deterioration Development Disease Down-Regulation Electrophysiology (science)Epilepsy Gene Mutation Genes Goals Hippocampus (Brain)Impaired cognition Impairment Injection of therapeutic agent Interneurons Intraventricular Memory Memory impairment Modeling Mutation Myoclonic Epilepsies Neurons Outcome Performance Pharmaceutical Preparations Physiological Play Procedures Process Property RNA Interference Rattus Role SCN1A protein Schedule Seizures Small Interfering RNA Sodium Channel Spatial Behavior Structure Syndrome System Testing Theta Rhythm Time Transfection cognitive function cognitive system critical period in vivo infancy information processing loss of function neuromechanism neuronal circuitry relating to nervous system research study treatment strategy voltage

项目摘要

DESCRIPTION (provided by applicant): Dravet Syndrome (DS) is a childhood epileptic disorder associated with profound cognitive impairments. DS has been associated in 80% of cases with mutations of the gene SCN1A coding for the voltage-gated sodium channel Nav1.1. 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 during which cognitive systems are permanently sensitive to the mutation effects. To approach this question, we have developed a transient model DS using RNA interference of Scn1a 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 the 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 aim 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. The second aim is to investigate 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 the septo-hippocampal network is well characterized, which makes it a model of predilection. The possibility that cognitive impairments may be caused by abnormal neuronal processing in addition to seizures would constitute a shift in the approach to DS. 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.

描述（由申请人提供）：Dravet 综合征 (DS) 是一种与严重认知障碍相关的儿童癫痫病。 80% 的 DS 病例与编码电压门控钠通道 Nav1.1 的基因 SCN1A 突变有关。 Nav1.1 在抑制性中间神经元中高度表达，正如我们在此辩护的那样，这不仅可以解释癫痫发作，还可以解释认知障碍。中间神经元通过控制动作电位和振荡活动的时间在信息处理中发挥关键作用。神经元回路的这些基本组成部分的改变可能会对神经处理产生深远的影响，从而对认知产生深远的影响。该提案的目标是研究导致认知障碍的生理机制，并确定是否存在认知系统对突变效应永久敏感的发育关键期。为了解决这个问题，我们在大鼠中使用 Scn1a 的 RNA 干扰开发了一个瞬时模型 DS。该过程在大鼠中诱导认知障碍但没有癫痫发作，并且可以针对特定结构并在特定发育时期启动。我们假设 NaV1.1 缺陷足以影响神经元编码、振荡活动和认知。我们还假设存在一个认知发展对 NaV1.1 异常特别敏感的关键时期。为了检验这些假设，我们将在执行记忆任务的大鼠中结合体内 RNA 干扰、脑电图 (EEG) 振荡的动态分析和单细胞电生理学（位置细胞）。该项目的首要目标是确定是否存在 NaV1.1 对认知发展至关重要的关键时期。我们将研究在产后发育的不同时期进行脑室内 siRNA 给药的急性和长期认知结果。第二个目的是研究 NaV1.1 减少导致认知障碍的神经机制。在这里，注射将集中在一个特定的结构，即隔海马区，这是大鼠空间记忆的神经基础。中间神经元在隔海马网络的生理特性中的作用已得到很好的表征，这使其成为偏爱的模型。除了癫痫发作之外，认知障碍可能是由神经元处理异常引起的，这可能会导致 DS 治疗方法的转变。这表明，除了传统的抗癫痫药物之外，可能还需要针对认知功能的其他治疗策略，以恢复受影响儿童的正常认知功能。