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: 10401489
• 负责人: Arena Abena Manning
• 金额: $ 4.12万
• 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/10401489
• 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 该提案调查了以下假设：两个最丰富的间神经元亚群体差异化 有助于毁灭性的线粒体相关癫痫症状疾病，称为利综合症 （LS）。以婴儿发作的癫痫发作为特征，通常是耐药且高度相关的 死亡过早，LS通常是由编码蛋白质的基因丧失功能突变引起的 在线粒体呼吸链的复合物I（CI）中。 NADH脱氢酶中隐性突变 （泛氨基酮）铁硫蛋白4（NDUFS4），它为CI内的结构蛋白进行编码，是最常见的 LS的原因，通常在LS病例中报告。尽管该综合征的机械基础仍然很差 理解的，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能中间神经元足以完全概括严重且经常致命的癫痫表型。 但是，这两个最丰富的间神经元亚型的相对贡献；表达白蛋白（PV） 或表达生长抑素的（SST）对癫痫表型的神经元仍然未知。另外， PV和SST中间神经元的独特解剖和生理特征相对较好 已建立的NDUFS4 KO的行为和功能后果仍然未知。解决这个问题 知识差距，我们将研究NDUFS4 KO的后果仅限于PV和SST中间神经元 单细胞，电路和整个动物的水平。基于PV的内在电生理特性 中间神经元和初步数据，我们假设仅PV中神经元中NDUFS4的条件删除 与SST中间神经元相比，将导致更严重的癫痫表型。这个奖学金培训计划需要 使用较高 体外和体内技术的质量。使用小鼠遗传学与行为，电生理学结合 和成像技术，这项工作有可能告知新颖，安全有效的发展 减轻耐药性癫痫的治疗策略，并延长患有患者的婴儿的寿命 LS。

项目成果

Elevated susceptibility to exogenous seizure triggers and impaired interneuron excitability in a mouse model of Leigh syndrome epilepsy.

• DOI: 10.1016/j.nbd.2023.106288
• 发表时间: 2023-10-15
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Manning, Arena;Han, Victor;Stephens, Alexa;Wang, Rose;Bush, Nicholas;Bard, Michelle;Ramirez, Jan M.;Kalume, Franck
• 通讯作者: Kalume, Franck