Translational medicine and mechanistic studies of brain neurophysiology in Fragile X Syndrome

在过去的六年里，我们的项目团队已经证明了神经生理学的异常 在脆性X综合征(FXS)小鼠和人类中都是保守的。这些发现涵盖了 物种提供了一个很好的机会来促进对临床相关的机械性理解 疾病特征和开发翻译生物标记物，并帮助治疗发现。这些 新的进展可以弥合临床前和临床成功之间的重大鸿沟 治疗的发展。我们采取机械性的方法来确定 跨越人、体内和前三个综合项目的神经生理学失调 活体小鼠研究。这允许从全脑网络建模到 微电路和分子分析有助于发现目标，同时提高翻译能力 FXS的药物努力。在这样做的过程中，我们强调认识到内部的异质性 FXS，并使用这一理解来建模如何最好地解释和连接临床前和临床 学习。出于对我们领域翻译工作面临的挑战的认识，我们有 开发了一种分析和解释神经生理学数据的同步方法 确保各研究平台的结果具有可比性。调查结果惊人的一致性 跨层次的调查和物种提供了前所未有的调查机会 在小鼠和人类研究中大脑功能障碍的机制因此显著改善 转化医学在FXS的发展机遇-这是一项多学科的任务， 非常适合中心环境。项目1(埃里克森/斯威尼；辛辛那提)将进行人类 FXS神经生理学、行为和药理学探针研究将继续深入 大脑皮质兴奋性和对刺激异常反应的神经生理学模型 也在寻求解决人类FXS的异质性。项目2(活页夹/Razak； Riverside)将在Fmr1 KO中为FXS开发翻译神经生理生物标记物 鼠标采用表面和深度两种多电极阵列技术。项目3(Huber/Gibson， 将研究神经生理学的微电路和分子机制 Fmr1KO小鼠的调节失调。所有项目都将审查候选机制 用药理学探针法检测神经生理学失调的机制 对小鼠和病人的平行研究感兴趣。

Over the last six years our project teams have demonstrated that neurophysiology abnormalities are conserved across mice and humans in fragile X syndrome (FXS). These findings across species provide a great opportunity to advance mechanistic understanding of clinically relevant illness features and develop translational biomarkers and aid treatment discovery. These advances can bridge the significant chasm between preclinical and clinical success in new treatment development. We take mechanistic approaches to determining the drivers of neurophysiology dysregulation across three integrated projects spanning human, in vivo, and ex vivo mouse study. This allows for levels of analysis from whole brain network modeling to microcircuit and molecular analysis to aid target discovery while improving translational medicine efforts in FXS. In doing this we place emphasis on recognizing heterogeneity within FXS and using this understanding to model how to best interpret and link preclinical and clinical study. Out of this appreciation of the challenges to translational efforts in our field, we have developed a synchronized approach to the analysis and interpretation of neurophysiology data ensuring comparable results across research platforms. The striking consistency of findings across levels of investigation and species offers an unprecedented opportunity to investigate mechanisms of brain dysfunction across mouse and human study thus significantly improving opportunities for translational medicine development in FXS- a multidisciplinary mission that is ideal for a Center environment. Project 1 (Erickson/Sweeney; Cincinnati) will conduct human FXS neurophysiology, behavior, and pharmacological probe studies to pursue advanced neurophysiology modeling of cortical hyperexcitability and abnormal response to stimuli while also seeking to resolve heterogeneity across FXS in humans. Project 2 (Binder/Razak; Riverside) will develop translational neurophysiological biomarkers for FXS in the Fmr1 KO mouse using both surface and depth multi-electrode array technology. Project 3 (Huber/Gibson, UTSW) will investigate the microcircuit and molecular mechanisms of neurophysiologic dysregulation in the Fmr1 KO mouse. All Projects will examine candidate mechanisms of neurophysiologic dysregulation with a pharmacological probe strategy to test mechanisms of interest in parallel studies of mice and patients.