Structural and behavioral impact of ASD-associated variants of NRXN1 in Drosophila melanogaster.

NRXN1 的 ASD 相关变体对果蝇的结构和行为影响。

• 批准号: 10261321
• 负责人: Jonathan Andrews
• 金额: $ 3.37万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2022-03-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261321
• 关键词: Adult; Affect; Aggressive behavior; Animals; Architecture; Attentional deficit; Axon; Behavior; Behavioral; Brain; Calcium Channel; Candidate Disease Gene; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cells; Child; Circadian Rhythms; Courtship; Defect; Development; Diagnosis; Disease; Drosophila genus; Drosophila melanogaster; Etiology; Frequencies; Generations; Genes; Genetic; Glutamates; Goals; Grooming; Growth; Health; Homologous Gene; Hour; Human; Knock-out; Length; Link; Maintenance; Mediating; Memory; Memory impairment; Methods; Modeling; Molecular; Morphology; Neurites; Neurobiology; Neurons; Pacemakers; Pathway interactions; Patients; Pattern; Periodicity; Phenotype; Play; Prevalence; Problem behavior; Production; Proteins; Reporting; Research; Resolution; Role; Schizophrenia; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Social Behavior; Source; Stereotyping; Structure; Symptoms; Synapses; Synaptic plasticity; System; Techniques; Time; Variant; Work; Youth; autism spectrum disorder; behavioral response; cell type; fly; improved; insight; knockin animal; mood regulation; nervous system disorder; neural circuit; neuronal circuitry; prevent; sleep pattern; sleep regulation; social space; synaptogenesis; synaptotagmin

Sleep disorders are common in patients diagnosed with autism spectrum disorders (ASD), being present in upward of 80% of ASD youths. The sleep disruptions frequently last into adulthood, but it has been difficult to elucidate a common neurobiological cause of these sleep disruptions. Previous research into this phenomenon has noted circadian rhythm defects, frequent nighttime waking, and an overall reduction in nighttime sleep: symptoms similar to what is reported in animal knock-out models of NRNX1, a synaptic plasticity gene implicated in ASD. NRXN1 is currently known to interact with post- synaptic proteins to stabilize synapses and promote neurite outgrowth, potentially acting as a common source for both sleep disruptions and for neurite overgrowth phenotypes observed in ASD. Therefore, identifying morphological changes in wake-promoting neurons during a cycling 24-hour time period will be a necessary precursor to identifying a common molecular pathway for both ASD and sleep disorders. In Drosophila, PDF neurons are an important part of the wake-promoting circuit, and are necessary for the generation of stable sleep patterns. Recently, it has been shown that PDF neurons undergo extensive remodeling, demonstrating cyclical periods of pruning and regrowth, over a 24 hour time period. While previous studies have demonstrated the presence of Nrx-1, the Drosophila homologue for NRXN1, in wake-promoting PDF neurons, it remains to be seen if the loss of Nrx-1 significantly impacts the remodeling cycle observed in healthy animals. As part of the proposed research, I will develop a Drosophila model of ASD by expressing human NRXN1 in a Nrx-1 null background. Specifically, I will evaluate if the loss of Nrx-1 significantly alters the cyclical remodeling of Drosophila PDF neurons, and whether this effect can be rescued by the expression of human reference NRXN1 or ASD-associated variant. I will then determine if this effect is sufficient to disrupt sleep bouts, variations in the circadian rhythm, or alterations in stereotyped social behavior. This proposed work will yield a new model with which to evaluate the effects of genes that contribute to synaptic plasticity and provide needed information about the neurobiology of both sleep and ASD.

睡眠障碍在诊断患有自闭症谱系障碍 (ASD) 的患者中很常见， 超过 80% 的 ASD 青少年。睡眠障碍经常持续到成年期，但 很难阐明这些睡眠中断的常见神经生物学原因。先前的研究 这种现象表明昼夜节律缺陷、频繁夜间醒来以及整体 夜间睡眠减少：症状与动物敲除模型中报道的相似 NRNX1，一种与自闭症谱系障碍有关的突触可塑性基因。目前已知 NRXN1 与后相互作用 突触蛋白可稳定突触并促进神经突生长，可能作为一种常见的 睡眠中断和自闭症谱系障碍中观察到的神经突过度生长表型的来源。所以， 识别 24 小时周期内促醒神经元的形态变化将 是确定自闭症谱系障碍和睡眠障碍的共同分子途径的必要前提。 在果蝇中，PDF 神经元是唤醒促进回路的重要组成部分，对于 稳定睡眠模式的产生。最近，研究表明 PDF 神经元经历 广泛的重塑，展示了 24 小时内修剪和再生的周期性周期 时期。虽然之前的研究已经证明了 Nrx-1 的存在，Nrx-1 是果蝇的同源物 NRXN1，在促进唤醒的 PDF 神经元中，Nrx-1 的缺失是否会显着影响还有待观察 在健康动物中观察到的重塑周期。 作为拟议研究的一部分，我将通过表达人类 NRXN1 来开发 ASD 果蝇模型 在 Nrx-1 空背景中。具体来说，我将评估 Nrx-1 的损失是否会显着改变周期性 果蝇 PDF 神经元的重塑，以及这种效应是否可以通过表达 人类参考 NRXN1 或 ASD 相关变异。然后我将确定这种效果是否足以 扰乱睡眠、昼夜节律变化或刻板社会行为的改变。这 拟议的工作将产生一个新的模型，用它来评估基因的影响，这些基因有助于 突触可塑性并提供有关睡眠和自闭症谱系障碍的神经生物学所需的信息。