Elucidating the contribution of interneuron subtypes in Leigh syndrome-related epilepsy

阐明中间神经元亚型在 Leigh 综合征相关癫痫中的作用

基本信息

批准号：
10319917
负责人：
Arena Abena Manning
金额：
$ 4.05万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2023-07-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319917
关键词：
3 year old Address Affect Anatomy Animal Model Animals Area Ataxia Automobile Driving Behavior Behavioral Brain Breathing Cells Cessation of life Characteristics Child Clinical Complex D Cells Data Development Disease Electrophysiology (science)Epilepsy Failure to Thrive Fellowship Fire - disasters Functional disorder Genes Genetic Goals Hippocampus (Brain)Imaging Techniques Impairment In Vitro Infant Interneuron function Interneurons Intractable Epilepsy Iron-Sulfur Proteins Knock-out Knowledge Laser Scanning Confocal Microscopy Leigh Disease Lesion Longevity Metabolic stress Mitochondria Mitochondrial Diseases Modeling Monitor Mus Mutation Myocardium NADH dehydrogenase (ubiquinone)Neurobiology Neurons Nuclear Organ Parvalbumins Pathogenesis Phenotype Physiological Play Predisposition Prognosis Property Proteins Recurrence Reporting Research Resistance Respiratory Chain Role Seizures Severities Somatostatin Structural Protein Symptoms Syndrome System Techniques Testing Tissues Training Work base cell type conditional knockout effective therapy in vivo infancy loss of function mutation mitochondrial dysfunction mouse genetics mouse model novel pediatric patients premature targeted treatment treatment strategy

项目摘要

PROJECT SUMMARY This proposal investigates the hypothesis that the two most abundant interneuron subpopulations differentially contribute to the devastating mitochondria-related epileptic encephaolomyopathy known as Leigh syndrome (LS). Characterized by infantile-onset epileptic seizures that are often treatment-resistant and highly associated with premature death, LS is commonly caused by loss-of-function mutations in genes that encode for proteins within Complex I (CI) of the mitochondrial respiratory chain. Recessive mutations in NADH dehydrogenase (ubiquinone) iron sulfur protein 4 (NDUFS4), which encodes for a structural protein within CI, is the most common cause of LS and is often reported in LS cases. Although a mechanistic basis for the syndrome remains poorly understood, exciting preliminary data using animal models has shown that the conditional deletion of Ndufs4 in all GABAergic interneurons is sufficient to fully recapitulate the severe and often fatal epilepsy phenotype. However, the relative contribution of the two most abundant interneuron subtypes; parvalbumin-expressing (PV) or somatostatin-expressing (SST) interneurons to the epileptic phenotype remains unknown. Additionally, while the distinct anatomical and physiological characteristics of PV and SST interneurons is relatively well established, the behavioral and functional consequences of the Ndufs4 KO remain unknown. To address this knowledge gap, we will study the consequences of the Ndufs4 KO restricted to PV and SST interneurons at the level of single cells, circuits and whole animals. Based on the intrinsic electrophysiological properties of PV interneurons and preliminary data, we hypothesize that the conditional deletion of Ndufs4 in only PV interneurons will lead to a more severe epilepsy phenotype compared to SST interneurons. This fellowship training plan entails elucidating implications of mitochondrial dysfunction in the context of neurobiology and genetics, using high quality in vitro and in vivo techniques. Using mouse genetics in combination with behavior, electrophysiology and imaging techniques, this work has the potential to inform the development of novel, safe and effective treatment strategies to alleviate treatment-resistant epilepsy and extend the life span of infants suffering from LS.

项目概要该提案研究了以下假设：两个最丰富的中间神经元亚群存在差异导致破坏性线粒体相关癫痫性脑肌病，即 Leigh 综合征（LS）。以婴儿期癫痫发作为特征，通常具有治疗耐药性且高度相关对于过早死亡，LS 通常是由编码蛋白质的基因功能丧失突变引起的线粒体呼吸链的复合物 I (CI) 内。 NADH 脱氢酶隐性突变（泛醌）铁硫蛋白 4 (NDUFS4)，编码 CI 内的结构蛋白，是最常见的 LS 的病因，并且经常在 LS 病例中报道。尽管该综合征的机制基础仍然很差理解，使用动物模型的令人兴奋的初步数据表明，Ndufs4 的条件删除所有 GABA 能中间神经元都足以完全重现严重且常常致命的癫痫表型。然而，两种最丰富的中间神经元亚型的相对贡献；表达小清蛋白 (PV) 或表达生长抑素（SST）的中间神经元对癫痫表型的影响仍不清楚。另外，虽然 PV和SST中间神经元的独特的解剖学和生理学特征相对较好虽然已经确定，但 Ndufs4 KO 的行为和功能后果仍然未知。为了解决这个问题知识差距，我们将研究 Ndufs4 KO 仅限于 PV 和 SST 中间神经元的后果单细胞、电路和整个动物的水平。基于PV固有的电生理特性中间神经元和初步数据，我们假设仅在 PV 中间神经元中条件性删除 Ndufs4 与 SST 中间神经元相比，会导致更严重的癫痫表型。该奖学金培训计划包括阐明线粒体功能障碍在神经生物学和遗传学背景下的影响，利用高高质量的体外和体内技术。将小鼠遗传学与行为、电生理学相结合和成像技术，这项工作有可能为新型、安全和有效的药物的开发提供信息缓解难治性癫痫并延长婴儿寿命的治疗策略 LS。