Mechanisms of neocortical and sensory hyperexcitability in Fragile X Syndrome

描述(申请人提供)：感觉过敏通常见于FXS患者和FXS小鼠模型-Fmr1基因敲除(KO)。最近的数据表明，这种异常源于感觉回路中的过度兴奋。我们已经证实，在Fmr1KO小鼠模型中，皮质微回路是超兴奋的，在Fmr1KO小鼠和FXS患者中，感觉反应增强。因此，对感觉敏感性的研究在临床上是有意义的，但也许更重要的是感觉系统研究的前景，以促进对新皮质回路中过度兴奋的机制和后果的理解，这可能是影响FXS中一系列知觉、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超兴奋性的生化信号机制，这些机制涉及我们和其他人已经发现的过程，可以在KO小鼠模型中详细研究，并在FXS患者中进行测试，为新的治疗开发奠定基础。在不同级别的研究和物种中发现惊人的一致性，为研究小鼠疾病模型中大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--这是一项多学科任务，对于中心的环境来说是理想的。我们的中心旨在通过紧密整合和高度新颖的科学翻译研究计划来追求这一目标。项目1(Huber/Gibson；UTSW；共同研究人员)将使用FXS小鼠模型的体外脑片来确定听觉新皮质功能障碍的细胞、分子和突触机制。项目2(Razak/Etheii/Binder；UCR；共同研究人员)将在体内研究FXS小鼠模型中的听觉感觉处理缺陷，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，联合研究员)将使用新的神经生理学策略调查FXS患者的听觉皮质处理缺陷。所有项目都将用一种急性药理学探测策略来检验感官过度兴奋的候选机制，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.