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

• 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
• 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

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.

项目摘要 这项提议调查了两个最丰富的中间神经元亚群差异的假设， 导致了毁灭性的癫痫性脑肌病，即利氏综合征， （LS）。特征为通常对治疗具有抵抗性且高度相关的癫痫发作 在过早死亡的情况下，LS通常是由编码蛋白质的基因的功能丧失突变引起的。 在线粒体呼吸链的复合物I（Cl）内。NADH脱氢酶的隐性突变 （泛醌）铁硫蛋白4（NDUFS 4），其编码CI内的结构蛋白，是最常见的 LS的原因，并经常在LS病例中报告。虽然该综合征的机制基础仍然很差 据了解，使用动物模型获得的令人兴奋的初步数据表明， 所有GABA能中间神经元足以完全再现严重且通常致命的癫痫表型。 然而，两个最丰富的中间神经元亚型的相对贡献;小白蛋白表达（PV） 或生长抑素表达（SST）的中间神经元的癫痫表型仍然未知。此外，虽然 PV和SST中间神经元的解剖学和生理学特征相对较好 虽然已经建立，但Ndufs 4 KO的行为和功能后果仍然未知。为了解决这个 知识的差距，我们将研究的后果Ndufs 4 KO限制PV和SST中间神经元在 单细胞、电路和整个动物的水平。根据PV的固有电生理特性， 根据PV中间神经元和初步数据，我们假设只有PV中间神经元中Ndufs 4的条件性缺失 将导致比SST中间神经元更严重的癫痫表型。这项研究金培训计划需要 使用高密度脂蛋白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 质量在体外和体内技术。利用小鼠遗传学结合行为电生理学 和成像技术，这项工作有可能为开发新的，安全有效的 缓解难治性癫痫和延长患有癫痫的婴儿寿命的治疗策略 LS.