Hyperexcitability and translational phenotypes in a preclinical model of SYNGAP1 mutations.
Hyperexcitability and translational phenotypes in a preclinical model of SYNGAP1 mutations.
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SYNGAP1 突变临床前模型中的过度兴奋性和翻译表型。
DOI：
10.1101/2023.07.24.550093
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Silverman,JillL
中科院分区：
文献类型：
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作者：
Fenton,TimothyA;Haouchine,OliviaY;Hallam,ElizabethL;Smith,EmilyM;Jackson,KiyaC;Rahbarian,Darlene;Canales,Cesar;Adhikari,Anna;Nord,AlexanderS;Ben-Shalom,Roy;Silverman,JillL
SYNGAP1 是神经元发育、突触结构和功能的关键基因。尽管罕见，但 SYNGAP1 的破坏会直接导致一种可遗传识别的神经发育障碍 (NDD)，称为 SYNGAP1 相关智力障碍。如果没有功能性 SynGAP1 蛋白，患者会出现智力障碍、运动障碍和癫痫。之前使用具有多种种系和条件突变的小鼠模型进行的研究有助于描述 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。SYNGAP1 的纯合性缺失具有胚胎致死性。 SynGAP1 的杂合突变会导致多种表型，包括运动活动增加、工作空间记忆受损、提示恐惧记忆受损和刻板行为增加。我们的体内功能数据使用 Huganir 实验室的原始种系突变小鼠系，证实了强烈的多动症以及学习和记忆缺陷。在这里，我们描述了睡眠转化生物标志物领域的损伤，利用无线遥测脑电图（EEG）收集的神经生理学数据来表征。我们发现Syngap1+/-小鼠除了功率升高之外，在数量和持续时间上也表现出升高的尖峰序列，最显着的是在Delta功率带中。使用高密度微电极阵列 (HD-MEA)，Syngap1+/- 小鼠的原代神经元表现出网络放电活动增加、每次爆发的峰值更大、峰值之间的爆发间隔更短。这项工作具有转化性、创新性和非常重要的意义，因为它概述了 Syngap1 突变小鼠的功能损伤。同时，这项工作利用了不受限制的无线神经生理学，可以发现 Syngap1R-ID 的潜在生物标志物，用于临床试验，就像对其他 NDD 所做的那样。我们的工作是 SynGAP1R-ID 转化工作的实质性进展，因为它在体内神经生理学大脑活动和功能中桥接了体外电生理神经元活动和功能。这些数据阐明了多种定量的体内和体外转化生物标志物，用于开发 SYNGAP1 相关智力障碍的治疗方法。
SYNGAP1is a critical gene for neuronal development, synaptic structure, and function. Although rare, the disruption ofSYNGAP1directly 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 ofSYNGAP1is embryonically lethal. Heterozygous mutations ofSynGAP1result in a broad range of phenotypes including increased locomotor activity, impaired working spatial memory, impaired cued fear memory, and increased stereotypic behavior. Ourin vivofunctional 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 discoveredSyngap1+/-mice exhibited elevated spike trains in both number and duration, in addition to elevated power, most notably in the delta power band. Primary neurons fromSyngap1+/-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 inSyngap1mutant 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 bridgesin-vitroelectrophysiological neuronal activity and function within vivoneurophysiological brain activity and function. These data elucidate multiple quantitative, translational biomarkersin vivoandin vitrofor the development of treatments for SYNGAP1-related intellectual disability.