Mechanisms of neocortical and sensory hyperexcitability in Fragile X Syndrome

描述（由申请方提供）：感觉超敏反应常见于FXS患者和FXS小鼠模型-Fmr 1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。我们已经确定，皮质微电路是过度兴奋的Fmr 1基因敲除小鼠模型，并在Fmr 1基因敲除小鼠和FXS患者的感觉反应增强。因此，感官敏感性的调查是临床相关的，但也许更重要的是感觉系统研究的承诺，以促进对新皮层回路中的过度兴奋的机制和后果的理解，这可能是影响FXS中广泛的感知，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是过度兴奋的基础的生化信号传导机制，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。研究水平和物种之间惊人的一致性为研究小鼠疾病模型中脑功能障碍的机制并将其直接转化为患者提供了前所未有的机会-这是一项多学科的使命，非常适合中心环境。我们中心的组织正是为了追求这一目标，具有紧密整合和高度新颖的转化研究科学计划。项目1（Huber/吉布森; UTSW;将使用FXS小鼠模型中的体外脑切片来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;共同研究者）将在FXS小鼠模型中研究体内听觉感觉处理缺陷，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，共同研究者）将使用新的神经生理学策略研究FXS患者的听觉皮层处理缺陷。所有项目将采用急性药理学探针策略检查感觉过度兴奋的候选机制，以在小鼠和患者的平行研究中测试感兴趣的机制。

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.