Mechanisms of neocortical and sensory hyperexcitability in Fragile X Syndrome

脆性 X 综合征的新皮质和感觉过度兴奋的机制

• 批准号: 9285824
• 负责人: KIMBERLY M. HUBER
• 金额: $ 173.41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9285824
• 关键词: Acute; Address; Auditory; Auditory area; Biochemical; Brain; Clinical; Clinical Investigator; Cognitive; Data; Development; Disease; Disease model; Distress; Electroencephalography; Electrophysiology (science); Employee Strikes; Endocannabinoids; Environment; Event-Related Potentials; FMR1; Foundations; Fragile X Syndrome; Frequencies; Functional disorder; Genes; Glutamates; Human; Hypersensitivity; Impairment; In Vitro; Individual; Investigation; Knock-out; Knockout Mice; Knowledge; Language; Lead; Link; Matrix Metalloproteinases; Measures; Mediating; Metabotropic Glutamate Receptors; Mission; Modality; Molecular; Mus; Neocortex; Neurons; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phenotype; Population; Problem behavior; Process; Regulation; Reporting; Research Personnel; Research Project Grants; Rest; Role; Sensory; Signal Transduction; Slice; Synapses; Testing; Therapeutic; Time; Translating; audiogenic seizure; auditory processing; base; brain dysfunction; clinically relevant; experimental study; gamma-Aminobutyric Acid; in vivo; interest; mouse model; multidisciplinary; neocortical; neural circuit; neurochemistry; neuromechanism; neurophysiology; novel; novel therapeutics; programs; public health relevance; receptive field; relating to nervous system; response; sensory mechanism; sensory system; skills; sound; stem; synergism; therapeutic candidate; therapeutic development; therapy development; translational research program

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.

描述（由申请人提供）：在FXS患者和FXS小鼠模型-FMR1敲除（KO）中通常可以看到感觉超敏反应。最近的数据表明，这种异常源于感觉电路的过度兴奋性。我们已经确定，在FMR1 KO小鼠模型中，皮质微电路可过度兴奋，并且在FMR1 KO小鼠和FXS患者中，感觉反应得到了增强。因此，对感觉敏感性的研究在临床上是相关的，但也许更重要的是，感觉系统研究的承诺可以提高对新皮质回路中过度兴奋性的机制和后果的理解，这可能代表了影响FXS中广泛的感知，认知能力和语言技能的主要病理生理因素。此外，我们已经确定了生化信号传导机制，这些机制可能是我们和其他人发现的过程中过度刺激性的基础，这些过程涉及我们和其他人可以在KO小鼠模型中进行详细检查，并在FXS患者中进行了测试，以开发新的治疗性发育的基础。调查水平和物种之间发现的惊人一致性为研究小鼠疾病模型中脑功能障碍的机制提供了前所未有的机会，并将其直接转化为患者 - 这是一个多学科的任务，非常适合中心环境。我们的中心组织以紧密整合且高度新颖的转化研究科学计划来准确追求这一目标。项目1（Huber/Gibson; UTSW；共同研究器）将在FXS小鼠模型中使用体外脑切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；共同研究器）将研究FXS小鼠模型中体内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较差。项目3（Sweeney/Byerly，UTSW，共同研究者）将使用FXS患者中的新型神经生理策略研究听觉皮质处理缺陷。所有项目都将通过急性药理探测策略检查感觉过度刺激性的候选机制，以测试小鼠和患者并行研究中感兴趣的机制。