Fenton Timothy A, Haouchine Olivia Y, Hallam Elizabeth L, Smith Emily M, Jackson Kiya C, Rahbarian Darlene, Canales Cesar, Adhikari Anna, Nord Alexander S, Ben-Shalom Roy, Silverman Jill L
bioRxiv. 2023 Jul 26:2023.07.24.550093. doi: 10.1101/2023.07.24.550093.
is a critical gene for neuronal development, synaptic structure, and function. Although rare, the disruption of directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability. Without functional SynGAP1 protein, patients present with intellectual disability, motor impairments, and epilepsy. Previous work using mouse models with a variety of germline and conditional mutations has helped delineate SynGAP1's critical roles in neuronal structure and function, as well as key biochemical signaling pathways essential to synapse integrity. Homozygous loss of is embryonically lethal. Heterozygous mutations of result in a broad range of phenotypes including increased locomotor activity, impaired working spatial memory, impaired cued fear memory, and increased stereotypic behavior. Our functional data, using the original germline mutation mouse line from the Huganir laboratory, corroborated robust hyperactivity and learning and memory deficits. Here, we describe impairments in the translational biomarker domain of sleep, characterized using neurophysiological data collected with wireless telemetric electroencephalography (EEG). We discovered mice exhibited elevated spike trains in both number and duration, in addition to elevated power, most notably in the delta power band. Primary neurons from mice displayed increased network firing activity, greater spikes per burst, and shorter inter-burst intervals between peaks using high density micro-electrode arrays (HD-MEA). This work is translational, innovative, and highly significant as it outlines functional impairments in mutant mice. Simultaneously, the work utilized untethered, wireless neurophysiology that can discover potential biomarkers of Syngap1R-ID, for clinical trials, as it has done with other NDDs. Our work is substantial forward progress toward translational work for SynGAP1R-ID as it bridges electrophysiological neuronal activity and function with neurophysiological brain activity and function. These data elucidate multiple quantitative, translational biomarkers and for the development of treatments for SYNGAP1-related intellectual disability.
是神经元发育、突触结构和功能的关键基因。虽然罕见，但 的破坏直接导致一种可通过基因识别的神经发育障碍（NDD），称为与SYNGAP1相关的智力残疾。没有功能性的SynGAP1蛋白，患者会出现智力残疾、运动障碍和癫痫。先前使用具有各种种系和条件性突变的小鼠模型的工作有助于阐明SynGAP1在神经元结构和功能中的关键作用，以及对突触完整性至关重要的关键生化信号通路。 的纯合缺失在胚胎期是致死的。 的杂合突变导致广泛的表型，包括运动活动增加、工作空间记忆受损、线索恐惧记忆受损和刻板行为增加。我们使用来自胡加尼尔实验室的原始种系突变小鼠品系的功能数据，证实了明显的多动以及学习和记忆缺陷。在这里，我们描述了睡眠翻译生物标志物领域的损伤，使用无线遥测脑电图（EEG）收集的神经生理学数据进行表征。我们发现 小鼠除了功率升高外，在数量和持续时间上的尖峰序列均升高，最明显的是在δ功率波段。使用高密度微电极阵列（HD-MEA），来自 小鼠的原代神经元显示出网络放电活动增加、每次爆发的尖峰更多以及峰之间的爆发间隔更短。这项工作具有转化性、创新性且非常重要，因为它概述了 突变小鼠中的功能损伤。同时，这项工作利用了无束缚的无线神经生理学，它可以像对其他NDDs所做的那样，发现Syngap1R-ID的潜在生物标志物用于临床试验。我们的工作在SynGAP1R-ID的转化工作方面取得了实质性的进展，因为它将电生理神经元活动和功能与神经生理脑活动和功能联系起来。这些数据阐明了多个定量的、用于与SYNGAP1相关智力残疾治疗开发的翻译生物标志物 和 。
