Sleep disturbances are a common comorbidity to most neurodevelopmental disorders and tend to worsen disease symptomatology. It is thus crucial to understand mechanisms underlying sleep disturbances to improve patients’ quality of life. Neuroligin-2 (NLGN2) is a synaptic adhesion protein regulating GABAergic transmission. It has been linked to autism spectrum disorders and schizophrenia in humans, and deregulations of its expression were shown to cause epileptic-like hypersynchronized cerebral activity in rodents. Importantly, the absence of Nlgn2 (knockout: KO) was previously shown to alter sleep-wake duration and quality in mice, notably increasing slow-wave sleep (SWS) delta activity (1–4 Hz) and altering its 24-h dynamics. This type of brain oscillation is involved in memory consolidation, and is also a marker of homeostatic sleep pressure. Sleep deprivation (SD) is notably known to impair cognition and the physiological response to sleep loss involves GABAergic transmission. Using electrocorticographic (ECoG) recordings, we here first aimed to verify how individual slow wave (SW; 0.5-4 Hz) density and properties (e.g., amplitude, slope, frequency) contribute to the higher SWS delta activity and altered 24-h dynamics observed in Nlgn2 KO mice. We further investigated the response of these animals to SD. Finally, we tested whether sleep loss affects the gene expression of Nlgn2 and related GABAergic transcripts in the cerebral cortex of wild-type mice using RNA sequencing. Our results show that Nlgn2 KO mice have both greater SW amplitude and density, and that SW density is the main property contributing to the altered 24-h dynamics. We also found the absence of Nlgn2 to accelerate paradoxical sleep recovery following SD, together with profound alterations in ECoG activity across vigilance states. Sleep loss, however, did not modify the 24-h distribution of the hypersynchronized ECoG events observed in these mice. Finally, RNA sequencing confirmed an overall decrease in cortical expression of Nlgn2 and related GABAergic transcripts following SD in wild-type mice. This work brings further insight into potential mechanisms of sleep duration and quality deregulation in neurodevelopmental disorders, notably involving NLGN2 and GABAergic neurotransmission.

中文翻译：

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Neuroligin-2 在慢波睡眠期间塑造个体慢波以及小鼠对睡眠剥夺的反应

睡眠障碍是大多数神经发育障碍的常见合并症，并且往往会使疾病症状恶化。因此，了解睡眠障碍的机制对于改善患者的生活质量至关重要。 Neuroligin-2 (NLGN2) 是一种调节 GABA 能传递的突触粘附蛋白。它与人类自闭症谱系障碍和精神分裂症有关，并且其表达失调被证明会导致啮齿类动物出现癫痫样超同步大脑活动。重要的是，之前的研究表明，Nlgn2（敲除：KO）的缺失会改变小鼠的睡眠-觉醒持续时间和质量，特别是增加慢波睡眠（SWS）δ活动（1-4 Hz）并改变其24小时动态。这种类型的大脑振荡涉及记忆巩固，也是稳态睡眠压力的标志。众所周知，睡眠剥夺 (SD) 会损害认知，而对睡眠不足的生理反应涉及 GABA 能传递。使用皮层电图 (ECoG) 记录，我们首先旨在验证个体慢波（SW；0.5-4 Hz）密度和属性（例如幅度、斜率、频率）如何导致更高的 SWS delta 活动和改变的 24 小时动态在 Nlgn2 KO 小鼠中观察到。我们进一步研究了这些动物对 SD 的反应。最后，我们使用RNA测序测试了睡眠不足是否影响野生型小鼠大脑皮层中Nlgn2和相关GABA能转录本的基因表达。我们的结果表明，Nlgn2 KO 小鼠具有更大的 SW 幅度和密度，并且 SW 密度是导致 24 小时动态改变的主要特性。我们还发现 Nlgn2 的缺失会加速 SD 后矛盾的睡眠恢复，以及不同警戒状态下 ECoG 活动的深刻变化。然而，睡眠不足并没有改变在这些小鼠中观察到的超同步 ECoG 事件的 24 小时分布。最后，RNA 测序证实野生型小鼠 SD 后 Nlgn2 和相关 GABA 能转录物的皮质表达总体下降。这项工作进一步深入了解了神经发育障碍中睡眠持续时间和质量失调的潜在机制，特别是涉及 NLGN2 和 GABA 能神经传递。