Network Mechanisms, Biomarkers and Pharmacology of Fragile X Syndrome in Humans

项目1摘要 在过去的6年里，我们脆性X综合征(FXS)研究联盟的人类研究部分 已经建立了与FXS中关键的感觉、认知和症状相关的神经生理学改变。 我们首次报道了大脑皮质过度兴奋性，表现为静息状态下伽马能量过多和 对听觉刺激做出适当的神经反应。我们证明了特征是并行守恒的 小鼠脑电实验(项目2小组)，并在大脑皮质切片内的体外记录中进一步探索 FMR1 KO鼠标(项目3团队)。我们已建立的合作代表着，如果不是最紧密的 研究FXS的综合工作台到床边研究计划。我们的中心假设是， 脆性X智力低下蛋白(FMRP)导致背景升高的皮质过度兴奋性 伽马频段功率和改变的跨频率调节过程。项目1的总体目标是 使用新的范例更好地阐明神经生理学改变的性质及其临床意义 和分析技术，将发现从感觉扩展到关联皮质，启动认知和 行为过程，使用我们的神经生理生物标记物来预测和跟踪对谷氨酸和 GABA能药物，并用大样本研究与以下相关的神经生理改变的异质性 遗传和人口统计特征。我们的目标是在患有FXS的成年人中进行网络神经生理学建模， 典型的发育和发育迟缓的匹配对照组受试者。在这项工作中，我们将评估 在FXS中改变的认知过程的神经生理学。此外，我们还将发展综合 对休息、感觉处理和认知活动期间的神经振荡变化进行建模。 我们的目标是在成人中进行新的安慰剂对照、单剂量、交叉机制的药物挑战研究。 使用FXS。这项药物挑战将集中在GABAB神经传递(阿巴氯芬)的小分子靶向， GABAA神经递质(Baer-101；前身为AZD7325)和NMDA谷氨酸能神经递质 (纪念碑)。我们将同时评估药物对神经生理学结果、行为和认知的影响。 在项目2中对Fmr1 KO小鼠进行相同药物的测试。第三，我们的目标是解决内部的异质性 人类FXS通过评估基于性别的FXS患者的神经生理、认知和临床特征， 马赛克状态和血液FMRP水平。我们还将评估神经生理学中与年龄相关的变异性， 青年FXS患者和健康对照的认知、临床特征的横断面研究 年龄范围。这些努力建立在我们迄今推动FXS转化医学努力的经验基础上，通过 确保与我们的临床前合作者的实验紧密联系。这确保了临床前的结果 工作可以向前翻译，同时我们的人类发现可以为临床前方法提供信息，以建立 新的治疗靶点和新的生物标记物，以加快FXS的药物发现。

Project 1 Abstract Over the past 6 years, the human research component of our Fragile X Syndrome (FXS) Research Consortium has established neurophysiological alterations linked to key sensory, cognitive, and symptom correlates in FXS. We first reported cortical hyperexcitability in the form of excessive gamma power at rest and a reduced ability to mount appropriate neural responses to auditory stimuli. We demonstrated that features are conserved in parallel murine EEG experiments (Project 2 team) and probed further in ex vivo recordings within cortical slices in the Fmr1 KO mouse (Project 3 team). Our established collaborations represent one of, if not the most tightly integrated bench to bedside research programs studying FXS. Our central hypothesis posits that the absence of fragile X mental retardation protein (FMRP) results in cortical hyperexcitability reflected in elevated background gamma band power and altered cross-frequency regulatory processes. The overarching aims of Project 1 are to better clarify the nature of neurophysiological alterations and their clinical implications using new paradigms and analytic techniques, extend findings from sensory to association cortex, initiate EEG studies of cognitive and behavioral processes, use our neurophysiological biomarkers to predict and track response to glutamatergic and GABAergic drugs, and with large samples investigate heterogeneity in neurophysiological alterations related to genetic and demographic features. We aim to pursue network neurophysiology modeling in adults with FXS, typically developing and developmentally delayed matched control subjects. In this work we will evaluate neurophysiology during cognitive processes that are altered in FXS. We will additionally develop integrated modeling of neural oscillatory alterations across rest, during sensory processing and during cognitive activity. We aim to conduct novel placebo-controlled, single-dose, crossover mechanistic drug challenge studies in adults with FXS. This drug challenge will focus on small molecule targeting of GABAB neurotransmission (arbaclofen), GABAA neurotransmission (BAER-101; formerly AZD7325), and NMDA glutamatergic neurotransmission (memantine). We will evaluate drug impact on neurophysiology outcomes, behavior, and cognition in parallel with testing of the same drugs in the Fmr1 KO mouse in Project 2. Third, we aim to resolve heterogeneity within human FXS by evaluating neurophysiological, cognitive, and clinical profiles in humans with FXS based on sex, mosaic status, and blood FMRP level. We will additionally evaluate age-related variability in neurophysiologic, cognitive, and clinical profiles in a cross-sectional study of patients with FXS and healthy controls in the youth age range. These efforts build on our experience to date moving forward FXS translational medicine efforts by ensuring tight linkages to the experiments of our preclinical collaborators. This ensures that results of preclinical work can be forward translated while in parallel our human findings can inform preclinical approaches to establish new therapeutic targets and novel biomarkers to speed drug discovery for FXS.