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

睡眠障碍在被诊断为自闭症谱系障碍(ASD)的患者中很常见 在80%以上的自闭症青少年中。睡眠障碍经常会持续到成年期，但它确实是 很难阐明这些睡眠障碍的常见神经生物学原因。先前对…的研究 这一现象已经注意到昼夜节律缺陷，夜间频繁醒来，以及 夜间睡眠减少：症状类似于在动物基因敲除模型中报告的 NRNX1，一个与ASD有关的突触可塑性基因。目前已知NRXN1与POST- 突触蛋白稳定突触并促进轴突生长，可能作为一种常见的 ASD中观察到的睡眠障碍和轴突过度生长表型的来源。因此， 识别24小时周期中促进觉醒的神经元的形态变化将 是确定ASD和睡眠障碍的共同分子途径的必要前驱。 在果蝇中，PDF神经元是觉醒促进电路的重要组成部分，是 稳定睡眠模式的产生。最近，研究表明，PDF神经元经历了 广泛的重塑，在24小时内表现出修剪和再生的周期性 句号。虽然之前的研究已经证明了NRX-1的存在，但果蝇的同源物 在促进觉醒的PDF神经元中，NRX-1的丢失是否会显著影响仍有待观察 在健康动物身上观察到的重塑周期。 作为拟议研究的一部分，我将通过表达人类NRXN1来开发ASD的果蝇模型 在NRX-1零背景下。具体地说，我将评估NRX-1的丧失是否显著改变了周期性 果蝇PDF神经元的重塑，以及这种影响是否可以通过表达 人类参考NRXN1或ASD相关变体。然后我将确定这一效果是否足以 扰乱睡眠，昼夜节律的变化，或陈规的社交行为的改变。这 拟议中的工作将产生一种新的模型，用来评估影响 突触可塑性，并提供有关睡眠和ASD的神经生物学所需的信息。

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.