Altered Dopamine Transporter Function in Autism

自闭症中多巴胺转运蛋白功能的改变

• 批准号: 9601214
• 负责人: Jenny Isabel Aguilar
• 金额: $ 1.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2020-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9601214
• 关键词: Altered; Dopamine; Transporter; Function; Autism

PROJECT SUMMARY Dopamine (DA) plays key roles in the central nervous system by regulating a variety of physiological states, including cognition, motivation, and attention. While DA dysfunction is known to be involved in several neuropsychiatric disorders, its role in the pathogenesis of Autism Spectrum Disorders (ASD) as well as comorbidities associated with ASD (e.g. Attention Deficit Hyperactivity Disorder) are largely unknown. The DA transporter (DAT) is a key constituent of DA signaling in the CNS and the principal regulator of DA homeostasis, mediating the active re-uptake of DA from the synapse following its release upon action potential depolarization. The research proposed focuses on understanding how rare variants (RVs) in the human DAT (hDAT) gene (SLC6A3) identified in several ASD subjects cause aberrant hDAT function and disrupted DA- associated behaviors. Importantly, this work will determine how RVs in hDAT support DA dysfunction, a complication associated with ASD. Our laboratory recently defined the first ASD identified de novo mutation in hDAT. This mutation located in the seventh transmembrane domain, a region critical to DA uptake and efflux, dramatically alters hDAT function both in vitro and in vivo. Notably, this de novo DAT mutation alters DA neurotransmission and DA-associated behaviors as observed in Drosophila melanogaster. The work presented in this proposal aims to create a novel set of discoveries exploiting the structural, functional and behavioral findings from the analysis of new hDAT variants identified in multiple individuals with ASD. We will (S.A. #1) engineer the hDAT ASD variants to determine their putative structural and functional deficits in heterologous expression systems. We will generate transgenic Drosophila lines expressing hDAT wildtype or hDAT variants specifically in DAergic neurons to determine the functional impairments of these hDAT variants in whole, intact Drosophila brains. We will use (S.A. #2) these transgenic Drosophila lines to evaluate the behavioral significance of hDAT dysfunction supported by these hDAT variants.

项目摘要 多巴胺（DA）通过调节多种生理状态在中枢神经系统中起关键作用， 包括认知、动机和注意力。虽然已知DA功能障碍涉及几种 神经精神障碍，其在自闭症谱系障碍（ASD）发病机制中的作用，以及 与ASD相关的合并症（例如注意缺陷多动障碍）在很大程度上尚不清楚。 DA转运蛋白（DAT）是中枢神经系统中DA信号转导的重要组成部分，也是DA的主要调节因子 稳态，介导DA在动作电位释放后从突触主动再摄取 去极化这项研究的重点是了解人类DAT中的罕见变异（RV） 在几个ASD受试者中鉴定的hDAT基因（SLC 6A 3）导致异常的hDAT功能和破坏的DA-受体阻滞剂。 相关的行为。重要的是，这项工作将确定hDAT中的RV如何支持DA功能障碍， 与ASD相关的并发症 我们的实验室最近定义了第一个ASD在hDAT中发现的从头突变。这种突变位于 第七跨膜结构域是DA摄取和外排的关键区域，显著改变hDAT功能 无论是在体外还是在体内。值得注意的是，这种新生DAT突变改变了DA神经传递和DA相关神经递质。 在果蝇中观察到的行为。本提案中提出的作品旨在创作一部小说 一系列发现，利用新hDAT分析的结构、功能和行为发现 在多个ASD患者中发现的变异。 我们将（S. A. #1）工程化hDAT ASD变体以确定其推定的结构和功能缺陷 在异源表达系统中。我们将产生表达野生型hDAT的转基因果蝇系， 或特异性地在DA能神经元中的hDAT变体，以确定这些hDAT的功能损伤 完整的果蝇大脑中的变异。我们将使用（S. A. #2）这些转基因果蝇系来评估 这些hDAT变体支持hDAT功能障碍的行为意义。