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Abstract：
BACKGROUND: Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABAAR) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABAARs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls.
METHODS: We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student\'s t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05.
RESULTS: Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation.
CONCLUSIONS: Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations.
METHODS: We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student\'s t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05.
RESULTS: Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation.
CONCLUSIONS: Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations.
摘要：
背景：睡眠障碍是神经发育障碍（NDD）中普遍存在且复杂的合并症。Dup15q综合征（重复15q11.2-13.1）是一种遗传性疾病，对自闭症和智力障碍等NDD具有高度渗透性，并且经常伴有睡眠模式的显着破坏。15q关键区域包含对大脑发育至关重要的基因，特别是UBE3A和一组γ-氨基丁酸A型受体（GABAAR）基因。我们先前描述了该综合征的电生理生物标志物，以Dup15q综合征个体的β振荡增强（12-30Hz）为标志，类似于由GABAAR的变构调制引起的脑电图（EEG）改变。那些患有Dup15q综合征的人在清醒休息状态和睡眠期间表现出增加的β振荡，他们表现出非常异常的NREM睡眠。这项研究旨在评估这些EEG特征的翻译有效性，并通过量化具有母体（matDp/小鼠）或父系（patDp/小鼠）遗传的染色体工程小鼠的睡眠生理学来深入研究它们的神经生物学基础15q11.2-13.1等效复制，和仅UBE3A基因重复的小鼠（Ube3a过表达小鼠；Ube3aOE小鼠），并将睡眠指标与各自的野生型（WT）同窝对照进行比较。
方法：我们收集了35名（23名男性，12名女性）12-24周龄matDp/+，patDp/+,Ube3aOE小鼠，和他们的WT同窝对照。我们量化了基线睡眠，睡眠碎片，睡眠状态期间的频谱功率动态，和睡眠剥夺后的恢复。在每一组中,使用方差分析（ANOVA）和student\t检验评估了Dup15q突变小鼠和WT同窝对照之间的区别。基因型和时间的影响通过重复测量方差分析来辨别，和显著性建立在p<0.05。
结果：我们的研究表明，在整个大脑状态下，matDp/+小鼠反映了在Dup15q综合征患者的临床脑电图中观察到的升高的β振荡表型。在matDp/+和Ube3aOE小鼠中，轻度发作后的睡眠发作时间显着减少。然而,Dup15q突变体和WT同窝小鼠之间的NREM睡眠保持不变，表明与人类临床表现的差异。此外,而在睡眠剥夺6小时后，matDp/+小鼠的β振荡持续增加，恢复NREM睡眠在所有组中保持不变，因此表明这些小鼠在控制睡眠-觉醒调节的基本过程中表现出韧性。
结论：机械和可翻译脑电图生物标志物的定量对于提高我们对NDD及其潜在病理生理学的理解至关重要。我们对Dup15q小鼠睡眠生理学的研究强调，β脑电图生物标志物具有很强的翻译效度，从而为推定药物靶标的临床前研究打开了大门，使用生物标志物作为药物-靶标参与的转化量度。未改变的NREM睡眠可能是由于小鼠和人类之间神经生物学的固有差异。这些细微的区别突出了Dup15q综合征中睡眠中断的复杂性，并强调需要全面理解，包括小鼠模型和临床群体之间的共同和不同特征。
方法：我们收集了35名（23名男性，12名女性）12-24周龄matDp/+，patDp/+,Ube3aOE小鼠，和他们的WT同窝对照。我们量化了基线睡眠，睡眠碎片，睡眠状态期间的频谱功率动态，和睡眠剥夺后的恢复。在每一组中,使用方差分析（ANOVA）和student\t检验评估了Dup15q突变小鼠和WT同窝对照之间的区别。基因型和时间的影响通过重复测量方差分析来辨别，和显著性建立在p<0.05。
结果：我们的研究表明，在整个大脑状态下，matDp/+小鼠反映了在Dup15q综合征患者的临床脑电图中观察到的升高的β振荡表型。在matDp/+和Ube3aOE小鼠中，轻度发作后的睡眠发作时间显着减少。然而,Dup15q突变体和WT同窝小鼠之间的NREM睡眠保持不变，表明与人类临床表现的差异。此外,而在睡眠剥夺6小时后，matDp/+小鼠的β振荡持续增加，恢复NREM睡眠在所有组中保持不变，因此表明这些小鼠在控制睡眠-觉醒调节的基本过程中表现出韧性。
结论：机械和可翻译脑电图生物标志物的定量对于提高我们对NDD及其潜在病理生理学的理解至关重要。我们对Dup15q小鼠睡眠生理学的研究强调，β脑电图生物标志物具有很强的翻译效度，从而为推定药物靶标的临床前研究打开了大门，使用生物标志物作为药物-靶标参与的转化量度。未改变的NREM睡眠可能是由于小鼠和人类之间神经生物学的固有差异。这些细微的区别突出了Dup15q综合征中睡眠中断的复杂性，并强调需要全面理解，包括小鼠模型和临床群体之间的共同和不同特征。
