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

睡眠障碍在诊断为自闭症谱系障碍（ASD）的患者中很常见， 在超过80%的自闭症青少年中睡眠中断经常持续到成年期，但它一直是 很难阐明这些睡眠中断的共同神经生物学原因。以前的研究 这种现象已经注意到昼夜节律的缺陷，频繁的夜间醒来， 夜间睡眠减少：症状类似于动物敲除模型中报告的 NRNX 1是一个与ASD有关的突触可塑性基因。目前已知NRXN 1与后 突触蛋白稳定突触和促进神经突生长，可能作为一个共同的 睡眠中断和ASD中观察到的神经突过度生长表型。因此，我们认为， 在24小时周期内识别促醒神经元的形态学变化将 这是确定ASD和睡眠障碍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，并且是必要的， 稳定睡眠模式的产生。最近，已经表明PDF神经元经历 广泛的重塑，表现出周期性的修剪和再生，超过24小时的时间 期虽然以前的研究已经证明了果蝇同源基因NATURAL-1的存在， NRXN 1，在唤醒促进PDF神经元，它仍然有待观察，如果NERXN 1的损失显着影响 在健康动物中观察到的重塑周期。 作为研究计划的一部分，我将通过表达人NRXN 1来建立ASD的果蝇模型 在一个NATURAL-1空背景下。具体来说，我将评估如果损失的仙女-1显着改变了周期性 果蝇PDF神经元的重塑，以及这种效应是否可以通过表达 人参考NRXN 1或ASD相关变体。然后，我将确定这种效果是否足以 扰乱睡眠，昼夜节律的变化，或改变刻板的社会行为。这 拟议的工作将产生一个新的模型，以评估基因的影响，有助于 突触可塑性，并提供睡眠和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.