ARX related Interneuron dysfunction and intractable pediatric epilepsy

ARX相关的中间神经元功能障碍和顽固性小儿癫痫

基本信息

批准号：
8049636
负责人：
ERIC D MARSH
金额：
$ 17.96万
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：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8049636
关键词：
Acute Adult Affect Age Age-Years Basic Science Behavioral Binding Biological Brain Carbachol Cells Child Childhood Clinical Cognitive Cognitive deficits Counseling Data Development Diagnosis Dyes Electroencephalography Encephalopathies Epilepsy Family Fostering Foundations Frequencies Functional disorder Future Generations Genetic Genotype Glutamates Goals Hippocampus (Brain)Homeobox Genes Imaging Techniques Impaired cognition In Situ Infantile spasms Interneurons Intractable Epilepsy Knockout Mice Lead Learning Life Link Little&apos s Disease Measures Memory Mental Retardation Modality Modeling Mus Mutant Strains Mice Mutation Neurologist Outcome Output Patients Pattern Pediatric Hospitals Pennsylvania Performance Phase Philadelphia Physiological Preparation Process Proteins Refractory Research Research Personnel Salinum Seizures Slice Syndrome Techniques Testing Time Training Universities Work base behavior test career career development cognitive function design disability knockout animal migration morris water maze mouse model novel prevent public health relevance research study response skills transcription factor voltage

项目摘要

DESCRIPTION (provided by applicant): The early epileptic encephalopathies are a group of syndromes characterized by intractable seizures, poor developmental outcome, and onset before six years of age. As a child neurologist specializing in pediatric epilepsy, I spend much of my clinical time counseling families whose children have these conditions. I find the conversations to be frustrating as I inform the families that our treatments are not designed for these diseases and little basic research exists to guide diagnosis and treatment. There is a pressing need for further research into the early intractable epilepsies. Developing models to study these syndromes is essential if advances in diagnosis and treatment are to be made. Recently, mutations in the aristaless-related homeobox gene (ARX), a developmental transcription factor, have been shown to cause X-linked infantile spasms syndrome and other early epileptic encephalopathies. Our experiments have shown that selective genetic deletion of Arx in interneurons (Arx CKO) results in abnormal migration of GABAergic interneurons, altered EEG activity, and spontaneous seizures. These data lead us to hypothesize that early loss of interneurons, in conditional Arx mice, alters the development of normal network function leading to intractable seizures and cognitive dysfunction modeling the early epileptic encephalopathies. This proposal both formulates experiments to examine the underlying pathophysiological processes of how interneuron dysfunction leads to seizures and encephalopathy as well as develops training opportunities to facilitate my transition to a career as an independent investigator. To study how Arx loss leads to seizures and mental retardation I first propose to determine the extent of circuit level dysfunction using a voltage sensitive dye imaging technique. Next, we will record and compare the development of control and Arx CKO mutant mice EEG and single unit activity during cortical and hippocampal rhythms to determine how rhythms are interrupted and which interneurons are involved. These studies will ascertain if interrupting interneuronal development alters the normal rhythms that bind cognitive processes. Finally, we will test the cognitive function of the mice, using a battery of behavioral techniques, to provide evidence linking circuit and network level dysfunction to the cognitive deficits of the mice. In addition to the proposed experiments, I have created a plan to help develop the skills needed for my transition to independence while working at the Children's Hospital of Philadelphia and the University of Pennsylvania. From these studies I will learn two techniques to implement in my future work. These studies will also set the foundation of a model to be used to understand how alterations in interneuronal development lead to an early epileptic encephalopathy. PUBLIC HEALTH RELEVANCE: Many children are stricken with a severe form of epilepsy early in life and go on to develop medically refractory seizures and severe cognitive deficits. Recently, mutations in ARX, a protein believed to control how interneurons develop, have been linked to families with an X-linked pattern of seizures and mental retardation. Using behavioral, EEG, and physiological techniques we will determine how loss of ARX disrupts normal brain function and leads to seizures and mental retardation.

描述（由申请人提供）：早期癫痫性脑病是一组以顽固性癫痫发作、发育结果差、六岁前发病为特征的综合征。作为一名专门研究小儿癫痫的儿童神经科医生，我花了很多临床时间为孩子患有这些疾病的家庭提供咨询。我发现这些谈话令人沮丧，因为我告诉家人我们的治疗方法不是针对这些疾病而设计的，而且很少有基础研究可以指导诊断和治疗。迫切需要对早期难治性癫痫进行进一步研究。如果要在诊断和治疗方面取得进展，开发模型来研究这些综合征至关重要。最近，aristaless 相关同源盒基因 (ARX)（一种发育转录因子）的突变已被证明可导致 X 连锁婴儿痉挛综合征和其他早期癫痫性脑病。我们的实验表明，中间神经元中 Arx 的选择性基因删除（Arx CKO）会导致 GABA 能中间神经元的异常迁移、脑电图活动改变和自发性癫痫发作。这些数据使我们推测，在有条件的 Arx 小鼠中，中间神经元的早期丢失会改变正常网络功能的发育，导致顽固性癫痫发作和认知功能障碍，从而模拟早期癫痫性脑病。该提案既制定了实验来检查中间神经元功能障碍如何导致癫痫发作和脑病的潜在病理生理过程，又提供了培训机会，以促进我向独立研究者的职业生涯过渡。为了研究 Arx 丢失如何导致癫痫发作和智力迟钝，我首先建议使用电压敏感染料成像技术来确定电路级功能障碍的程度。接下来，我们将记录并比较对照小鼠和 Arx CKO 突变小鼠脑电图的发育情况以及皮质和海马节律期间的单个单位活动，以确定节律如何被中断以及涉及哪些中间神经元。这些研究将确定中断中间神经元发育是否会改变与认知过程相关的正常节律。最后，我们将使用一系列行为技术来测试小鼠的认知功能，以提供将回路和网络水平功能障碍与小鼠认知缺陷联系起来的证据。除了拟议的实验之外，我还制定了一项计划，以帮助我在费城儿童医院和宾夕法尼亚大学工作期间培养过渡到独立所需的技能。从这些研究中，我将学到两种在我未来的工作中实施的技术。这些研究还将为用于了解神经元间发育的改变如何导致早期癫痫性脑病的模型奠定基础。公共卫生相关性：许多儿童在生命早期就患有严重的癫痫症，并继续发展为难治性癫痫发作和严重的认知缺陷。最近，ARX（一种被认为控制中间神经元发育的蛋白质）的突变与 X 连锁癫痫和智力低下模式的家族有关。使用行为、脑电图和生理技术，我们将确定 ARX 的缺失如何扰乱正常的大脑功能并导致癫痫发作和智力低下。