Mechanisms of neocortical and sensory hyperexcitability in Fragile X Syndrome

描述（由申请人提供）：感觉超敏反应常见于FXS患者和FXS小鼠模型- Fmr1敲除（KO）。最近的数据表明，这种异常源于感觉回路的过度兴奋性。我们已经证实，在Fmr1 KO小鼠模型中，皮质微回路是超兴奋的，并且Fmr1 KO小鼠和FXS患者的感觉反应增强。因此，对感觉敏感性的研究具有临床意义，但也许更重要的是，感觉系统研究有望促进对新皮层回路中高兴奋性的机制和后果的理解，这可能是影响FXS中广泛的知觉、认知和语言技能发展的主要病理生理因素。此外，我们已经确定了可能导致高兴奋性的生化信号机制，涉及我们和其他人已经发现的过程，可以在KO小鼠模型中进行详细检查，并在FXS患者中进行测试，为新的治疗开发奠定基础。研究结果在不同水平和不同物种之间的惊人一致性为研究小鼠疾病模型中的脑功能障碍机制并将其直接转化为患者提供了前所未有的机会——这是一个多学科的任务，是中心环境的理想选择。我们中心的组织正是为了实现这一目标，通过一个紧密整合和高度新颖的科学项目的转化研究。项目1 （Huber/Gibson； UTSW；合作者）将利用FXS小鼠模型的离体脑切片确定听觉新皮层功能障碍的细胞、分子和突触机制。项目2 （Razak/Etheii/Binder； UCR；合作研究者）将在FXS小鼠模型中研究听觉感觉加工缺陷，测试机制，并检查这些缺陷的发育和结构相关性。项目3 （Sweeney/Byerly， UTSW，合作研究者）将使用新的神经生理策略研究FXS患者的听觉皮质加工缺陷。所有项目将用急性药理学探针策略检查感觉超兴奋性的候选机制，以测试小鼠和患者平行研究中感兴趣的机制。

DESCRIPTION (provided by applicant): Sensory hypersensitivity is commonly seen in FXS patients and the FXS mouse model - the Fmr1 knockout (KO). Recent data suggests that this abnormality stems from hyperexcitability in sensory circuits. We have established that cortical microcircuits are hyperexcitable in the Fmr1 KO mouse model, and that sensory responses are enhanced in Fmr1 KO mice and FXS patients. Thus, investigation of sensory sensitivities is clinically relevant, but perhaps more important is the promise of sensory system studies to advance understanding of the mechanisms and consequences of hyperexcitability in neocortical circuitry that could represent a primary pathophysiological factor impacting the development of a wide range of perceptual, cognitive, and language skills in FXS. Further, we have identified biochemical signaling mechanisms that may underlie hyperexcitability involving processes that we and others have uncovered that can be examined in detail in KO mouse models and tested in FXS patients to develop a foundation for novel therapeutic development. The striking consistency of findings across levels of investigation and species offers an unprecedented opportunity to investigate mechanisms of brain dysfunction in a mouse disease model and translate it directly to patients - a multidisciplinary mission that is ideal for a Center environment. Our Center is organized to pursue precisely this aim with a tightly integrated and highly novel scientific program of translational research. Project 1 (Huber/Gibson; UTSW; co-investigators) will determine the cellular, molecular and synaptic mechanisms of auditory neocortical dysfunction using in vitro brain slices in FXS mouse models. Project 2 (Razak/Etheii/Binder; UCR; co-investigators) will study auditory sensory processing deficits in vivo in FXS mouse models, test mechanisms, and examine developmental and structural correlates of these deficits. Project 3 (Sweeney/Byerly, UTSW, co-investigators) will investigate auditory cortical processing deficits using novel neurophysiological strategies in individuals with FXS. All Projects will examine candidate mechanisms of sensory hyperexcitability with an acute pharmacological probe strategy to test mechanisms of interest in parallel studies of mice and patients.