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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：
8728339
负责人：
ERIC D MARSH
金额：
$ 36.27万
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/8728339
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）：在与幼儿癫痫发作和智力残疾有关的机制的知识方面存在广泛的差距