Institute for Biology/Genetics, Freie Universität Berlin, Takustraße 6, 14195 Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Germany.
Institute for Biology/Genetics, Freie Universität Berlin, Takustraße 6, 14195 Berlin, Germany.
Curr Biol. 2020 Mar 23;30(6):1077-1091.e5. doi: 10.1016/j.cub.2020.01.019. Epub 2020 Mar 5.
Sleep is universal across species and essential for quality of life and health, as evidenced by the consequences of sleep loss. Sleep might homeostatically normalize synaptic gains made over wake states in order to reset information processing and storage and support learning, and sleep-associated synaptic (ultra)structural changes have been demonstrated recently. However, causal relationships between the molecular and (ultra)structural status of synapses, sleep homeostatic regulation, and learning processes have yet to be established. We show here that the status of the presynaptic active zone can directly control sleep in Drosophila. Short sleep mutants showed a brain-wide upregulation of core presynaptic scaffold proteins and release factors. Increasing the gene copy number of ELKS-family scaffold master organizer Bruchpilot (BRP) not only mimicked changes in the active zone scaffold and release proteins but importantly provoked sleep in a dosage-dependent manner, qualitatively and quantitatively reminiscent of sleep deprivation effects. Conversely, reducing the brp copy number decreased sleep in short sleep mutant backgrounds, suggesting a specific role of the active zone plasticity in homeostatic sleep regulation. Finally, elimination of BRP specifically in the sleep-promoting R2 neurons of 4xBRP animals partially restored sleep patterns and rescued learning deficits. Our results suggest that the presynaptic active zone plasticity driven by BRP operates as a sleep homeostatic actuator that also restricts periods of effective learning.
睡眠是普遍存在于各个物种中的，对生活质量和健康至关重要，这一点可以从睡眠不足的后果中得到证明。睡眠可能通过使突触的增益在清醒状态下进行自我平衡，从而重置信息处理和存储，并支持学习，最近已经证明了与睡眠相关的突触（超微）结构变化。然而，突触的分子和（超微）结构状态、睡眠的自我平衡调节以及学习过程之间的因果关系尚未建立。我们在这里表明，突触前活跃区的状态可以直接控制果蝇的睡眠。短睡眠突变体表现出全脑核心突触支架蛋白和释放因子的上调。增加 ELKS 家族支架主组织者 Bruchpilot（BRP）的基因拷贝数不仅模拟了活跃区支架和释放蛋白的变化，而且重要的是以剂量依赖的方式引起了睡眠，在质量和数量上都类似于睡眠剥夺的影响。相反，在短睡眠突变体背景下降低 brp 拷贝数会减少睡眠，这表明活跃区可塑性在自我平衡睡眠调节中具有特定作用。最后，在 4xBRP 动物的促进睡眠的 R2 神经元中特异性消除 BRP 部分恢复了睡眠模式并挽救了学习缺陷。我们的研究结果表明，BRP 驱动的突触前活跃区可塑性作为睡眠自我平衡的执行器，也限制了有效的学习时间。
