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

项目总结 这一建议调查了两个最丰富的中间神经元亚群不同的假设 导致被称为Leigh综合征的破坏性线粒体相关癫痫脑肌肉病 (LS)。以婴儿发作性癫痫发作为特征的，这种癫痫发作通常是难治性的和高度相关的 在过早死亡的情况下，LS通常是由编码蛋白质的基因功能丧失突变引起的 在线粒体呼吸链的复合体I(CI)内。NADH脱氢酶的隐性突变 (泛醌)铁硫蛋白4(NDUFS4)是最常见的，它编码CI中的一种结构蛋白 LS的病因，常见于LS病例。尽管该综合征的机制基础仍然很差 可以理解的是，使用动物模型的令人兴奋的初步数据表明，在 所有GABA能中间神经元足以完全概括严重且往往致命的癫痫表型。 然而，两种最丰富的中间神经元亚型：小白蛋白表达(PV)的相对贡献。 或生长抑素表达(SST)的中间神经元对癫痫的表型尚不清楚。此外，虽然 PV和SST中间神经元具有明显的解剖和生理特征。 Ndufs4 KO的行为和功能后果尚不清楚。要解决这个问题 知识缺口，我们将研究Ndufs4 KO仅限于PV和SST中间神经元的后果 单个细胞、回路和整个动物的水平。基于光伏固有的电生理特性 中间神经元和初步数据，我们假设Ndufs4的条件性缺失只存在于PV中间神经元 与SST中间神经元相比，会导致更严重的癫痫表型。这项团契培训计划需要 用HIGH阐明神经生物学和遗传学背景下线粒体功能障碍的含义 体外和体内质量检测技术。将小鼠遗传学与行为、电生理学相结合 和成像技术，这项工作具有潜在的通知开发新颖，安全和有效 减轻难治性癫痫和延长婴儿寿命的治疗策略 LS.

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.