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：
8997125
负责人：
Pierre Pascal Lenck-Santini
金额：
$ 33.36万
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 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8997125
关键词：
ARHGEF5 gene Action Potentials Acute Adult Affect Age Alzheimer&apos 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 development 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 spatial memory support network treatment strategy voltage

项目摘要

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。编码 Nav 1.1 型的 SCN1A 基因突变会导致 Dravet 综合症 (DS)，这是一种严重的儿童期综合症与严重认知障碍相关的癫痫症。 SCN1A突变也已被描述在自闭症中，Nav1.1 的水平降低在各种阿尔茨海默病 (AD) 模型中都被观察到。导航1.1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，它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时间在信息处理中发挥着关键作用动作电位和振荡活动。神经元回路的这些基本组成部分的改变可能对神经处理和认知产生深远的影响。该提案的目标是研究导致认知障碍和认知障碍的生理机制确定是否存在认知系统对认知系统永久敏感的发展关键时期突变效应。为了解决这个问题，我们开发了一种暂时抑制 Nav1.1 的技术使用 RNA 干扰在大鼠中表达。该过程引起了认知障碍，但没有癫痫发作大鼠，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特别重要的关键时期对 NaV1.1 异常敏感。为了检验这些假设，我们将结合体内 RNA 干扰、电动力学分析执行记忆的大鼠的脑电图 (EEG) 振荡和单细胞电生理学（位置细胞）任务。该项目的第一部分将确定是否存在 NaV1.1 至关重要的关键时期用于认知发展。我们将研究脑室内的急性和长期认知结果 siRNA 给药在出生后发育的不同时期进行。在第二个目标中调查 NaV1.1 减少导致认知障碍的神经机制。在这里，注射将专注于一个特定的结构，即隔海马区，它是空间记忆的神经基础在老鼠身上。中间神经元在该网络的生理特性中的作用已得到很好的表征，使得一个理想的调查网络。除了以下原因之外，认知障碍也可能是由异常的神经元处理引起的癫痫发作将构成 DS 和其他儿童癫痫病治疗方法的范式转变认知结果不佳。这建议关注认知功能的额外治疗策略，可能需要使用传统抗癫痫药物以外的药物来恢复受影响患者的正常认知功能孩子们。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bad Timing for Epileptic Networks: Role of Temporal Dynamics in Seizures and Cognitive Deficits.

DOI：
10.1177/15357597211001877
发表时间：
2021-03-16
期刊：
Epilepsy currents
影响因子：
3.6
作者：
Lenck-Santini PP
通讯作者：
Lenck-Santini PP

Emergence of Coordinated Activity in the Developing Entorhinal-Hippocampal Network.

发育中的内嗅-海马网络中协调活动的出现。

DOI：
10.1093/cercor/bhy309
发表时间：
2019
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
0
作者：
Valeeva,Guzel;Janackova,Sona;Nasretdinov,Azat;Rychkova,Veronika;Makarov,Roman;Holmes,GregoryL;Khazipov,Roustem;Lenck-Santini,Pierre-Pascal
通讯作者：
Lenck-Santini,Pierre-Pascal

Focal Dorsal Hippocampal Nav1.1 Knock Down Alters Place Cell Temporal Coordination and Spatial Behavior.