Department of Neurology, University of Arizona Health Sciences, Tucson, AZ, USA.
Center for Insect Science, University of Arizona, Tucson, AZ, USA.
J Neurogenet. 2021 Mar;35(1):1-22. doi: 10.1080/01677063.2020.1833005. Epub 2020 Nov 9.
Mutations in hundreds of genes cause neurodevelopmental disorders with abnormal motor behavior alongside cognitive deficits. Boys with fragile X syndrome (FXS), a leading monogenic cause of intellectual disability, often display repetitive behaviors, a core feature of autism. By direct observation and manual analysis, we characterized spontaneous-motor-behavior phenotypes of mutants, an established model for FXS. We recorded individual 1-day-old adult flies, with mature nervous systems and prior to the onset of aging, in small arenas. We scored behavior using open-source video-annotation software to generate continuous activity timelines, which were represented graphically and quantitatively. Young mutants spent excessive time grooming, with increased bout number and duration; both were rescued by transgenic wild-type . By two grooming-pattern measures, -mutant flies showed elevated repetitions consistent with perseveration, which is common in FXS. In addition, the mutant flies display a preference for grooming posterior body structures, and an increased rate of grooming transitions from one site to another. We raise the possibility that courtship and circadian rhythm defects, previously reported for mutants, are complicated by excessive grooming. We also observed significantly increased grooming in mutants, despite their dramatically decreased walking phenotype. The mutant flies, a model for human -related neurodevelopmental disorders, displayed consistently elevated grooming indices throughout the assay, but transient locomotory activation immediately after placement in the arena. Based on published data identifying FMRP-target transcripts and functional analyses of mutations causing human genetic neurodevelopmental disorders, we propose the following proteins as candidate mediators of excessive repetitive behaviors in FXS: CaMKIIα, NMDA receptor subunits 2A and 2B, NLGN3, and SHANK3. Together, these fly-mutant phenotypes and mechanistic insights provide starting points for drug discovery to identify compounds that reduce dysfunctional repetitive behaviors.
数百个基因的突变导致神经发育障碍，伴有运动行为异常和认知缺陷。脆性 X 综合征（FXS）的男孩，一种主要的遗传性智力障碍原因，经常表现出重复行为，这是自闭症的一个核心特征。通过直接观察和手动分析，我们对突变体进行了自发运动行为表型的特征描述，突变体是 FXS 的一种成熟模型。我们记录了单个 1 日龄成年蝇的行为，此时它们的神经系统已经成熟，并且在衰老之前，在小竞技场中。我们使用开源视频注释软件对行为进行评分，以生成连续的活动时间线，并以图形和定量的方式表示。年轻的突变体过度修饰，修饰次数和持续时间增加；通过转染野生型可以挽救这两种情况。通过两种修饰模式的测量，突变体的重复次数增加，表现出坚持性，这在 FXS 中很常见。此外，突变体苍蝇还表现出对后体结构修饰的偏好，以及从一个部位到另一个部位修饰的过渡率增加。我们提出了这样的可能性，即先前报道的 突变体的求偶和昼夜节律缺陷，可能因过度修饰而变得复杂。我们还观察到突变体的修饰明显增加，尽管它们的行走表型急剧减少。突变体苍蝇是一种与人类相关的神经发育障碍模型，在整个试验中始终显示出升高的修饰指数，但在放入竞技场后立即出现短暂的运动激活。基于已发表的数据确定 FMRP 靶转录本和导致人类遗传性神经发育障碍的突变的功能分析，我们提出以下蛋白质作为 FXS 中过度重复行为的候选介质：CaMKIIα、NMDA 受体亚基 2A 和 2B、NLGN3 和 SHANK3。这些苍蝇突变体表型和机制见解为药物发现提供了起点，以确定减少功能失调的重复行为的化合物。
