Seizure generation and network excitability in Arx related Infantile Spasms

Arx 相关婴儿痉挛症中的癫痫发作和网络兴奋性

基本信息

批准号：
8631719
负责人：
ERIC D MARSH
金额：
$ 36.64万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631719
关键词：
Address Affect Age Area Behavioral Brain Brain region Cell Nucleus Cells Child Data Development Developmental Disabilities Disease Dyes Electrodes Electroencephalography Encephalopathies Epilepsy Family Foundations Frequencies Functional disorder GABA Agonists GCG gene Generations Genes Goals Hippocampus (Brain)Human Hypsarrhythmia Image Infantile spasms Intellectual functioning disability Interneurons Knowledge Lead Life Live Birth Location Malignant - descriptor Maps Measures Modeling Mus Mutation Outcome Output Pathology Pattern Pharmaceutical Preparations Phenotype Pyramidal Cells Research Research Design Resistance Role Seizures Series Slice Spasm Structure Syndrome Testing Thalamic structure Therapeutic Time Transgenic Mice Variant Work cell type disability effective therapy induced pluripotent stem cell infancy mouse model network dysfunction new therapeutic target novel novel therapeutics patch clamp polyalanine postnatal public health relevance ranpirnase research study therapeutic target translational study voltage young adult

项目摘要

DESCRIPTION (provided by applicant): There is an extensive gap in the knowledge of the mechanisms involved in generating seizures and intellectual disabilities in children with infantile spasms syndrome (ISS), one of the early epileptic encephalopathies. Infantile spasms, a malignant disorder affecting 1:2000 live births, results in the majority of children developing medication resistant seizures and severe developmental disabilities. Infantile spasms syndrome consists of epileptic spasms, an EEG pattern of hypsarrhythmia and developmental stagnation. This condition results in innumerable hardships to the families and life long disabilities to the child. Currently, there is no treatment truly specific for ISS or any early epileptic encephalopathies. Consequently, there is a pressing need for further research into the mechanisms of these conditions. We are proposing to elucidate the mechanisms of one model of infantile spasms. Our model, a transgenic mouse with a polyalanine expansion mutation in the Arx gene (Arx(GCG)7/Y), is the most common mutation in children with ARX related ISS and recapitulates much of the clinically observed seizure and behavioral phenotype. This is the only model that mimics a known human insult. The studies proposed test our hypothesis that changes in Arx during development alter both interneuron development and function resulting in hyperexcitable local networks and seizures that change as the mouse develops. Our preliminary data demonstrates hyperexcitability in the DG and CA3, and loss of inhibition onto CA1 pyramidal cells. To extend these findings and elucidate the mechanisms of infantile spasms, three series of experiments are proposed. First local network dysfunction will be determined at different ages using voltage sensitive dye (VSD) imaging and multielectrode recordings (MEA) of infantile and young adult Arx(GCG)7/Y mice. As our preliminary data establishes increased activity in the DG and CA3 regions of the hippocampus, we will attempt to locally rescue the phenotype by application of GABA agonists directly into CA3 and the DG. Next, we will determine the mechanisms behind the network changes found in Aim 1 by patch clamp recording both pyramidal cells and interneurons and quantifying the alterations in baseline and evoked activity between the Arx(GCG)7/Y and control mice. Finally, we will determine if there are local network changes outside the hippocampus by studying the thalamocortical circuitry in the Arx(GCG)7/Y and control mice. The rationale guiding the proposed experiments is by defining the mechanisms involved in generating seizures in a defined model of ISS, specific therapies can be developed to target these mechanisms. Hence, the knowledge obtained from the proposed studies will be the foundation for the translational studies that design novel therapeutics for these devastating conditions.

描述（由申请人提供）：了解婴儿儿童的癫痫发作和智力障碍所涉及的机制存在很大的差距痉挛综合征（ISS），早期的癫痫性脑病之一。婴儿痉挛是一种影响1：2000活产的恶性疾病，导致大多数儿童患有药物抗药性癫痫发作和严重的发育障碍。婴儿痉挛综合征由癫痫痉挛，催眠症和发育停滞的脑电图模式组成。这种条件给孩子带来了无数的艰辛和生命的残疾。目前，没有真正针对ISS或任何早期癫痫性脑病的治疗方法。因此，迫切需要进一步研究这些条件的机制。我们提议阐明一种婴儿痉挛模型的机制。我们的模型是ARX基因（ARX（GCG）7/Y）中具有多酰氨酸膨胀突变的转基因小鼠，是ARX相关ISS儿童中最常见的突变，并概括了许多临床上观察到的癫痫发作和行为表型。这是模仿已知人类侮辱的唯一模型。研究提出了我们的假设，即在发育过程中ARX的变化改变了中间神经元的发育和功能，从而导致了过度兴奋的局部网络以及随着小鼠的发展而变化的癫痫发作。我们的初步数据表明DG和CA3中的过度兴奋性，以及对CA1锥体细胞的抑制作用丧失。为了扩展这些发现并阐明婴儿痉挛的机制，提出了三个系列实验。使用电压敏感染料（VSD）成像和多电极记录（MEA）的婴儿ARX和年轻成人ARX（GCG）7/y小鼠，将在不同年龄的不同年龄确定第一个局部网络功能障碍。随着我们的初步数据在海马的DG和CA3区域的活性增加时，我们将尝试通过将GABA激动剂直接应用于CA3和DG来局部拯救表型。接下来，我们将通过贴片夹记录锥体细胞和中间神经元的贴片夹在AIM 1中发现的网络变化的机制，并量化基线的变化，并在ARX（GCG）7/y和对照小鼠之间诱发活性。最后，我们将通过研究ARX（GCG）7/y和对照小鼠中的丘脑皮层电路来确定海马之外的局部网络变化。指导提出的实验的基本原理是定义在确定的ISS模型中产生癫痫发作的机制，可以开发特定的疗法以靶向这些机制。因此，从拟议的研究中获得的知识将是翻译研究的基础，这些研究为这些毁灭性的条件设计了新颖的治疗剂。