Visual Circuit Regression and its Rescue in RTT Mouse Models

RTT 小鼠模型中的视觉回路回归及其拯救

• 批准号: 8888522
• 负责人: Chinfei Chen
• 金额: $ 55.95万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888522
• 关键词: Acute; Address; Adult; Age; Autistic Disorder; Behavior; Behavioral; Behavioral Assay; Bipolar Disorder; Brain; Breathing; Cells; Childhood; Cognition; Defect; Development; Diagnosis; Disease; Epilepsy; Equilibrium; Exhibits; Functional disorder; Genes; Health; Human; Impairment; In Vitro; Intervention; Laboratories; Language; Lead; Life; Measures; Methyl-CpG-Binding Protein 2; Modality; Modeling; Motor; Mus; Mutation; Nervous System Physiology; Neurodevelopmental Disorder; Neurons; Parvalbumins; Phase; Phenotype; Process; Recovery; Rett Syndrome; Role; Schizophrenia; Secondary to; Sensory; Sensory Process; Social Interaction; Staging; Symptoms; System; Testing; Thalamic structure; Time; Vision; Visual; Visual Cortex; Work; cognitive skill; critical developmental period; critical period; design; experience; hippocampal pyramidal neuron; in vivo; insight; mouse model; neural circuit; neuronal circuitry; novel strategies; postnatal; prevent; public health relevance; research study; restoration; retinogeniculate; sensory system; skills; social communication; visual information

 DESCRIPTION (provided by applicant): Rett syndrome (RTT), a devastating pediatric disorder, is caused by de-novo mutations in the MECP2 gene. The key feature and basic requirement for Rett syndrome diagnoses is the loss of acquired skills or regression, occurring between the ages of 1.5 and 4-5 years after an apparent initial normal development. Once regression is complete, it was thought that the symptoms were irreversible in adults. Mice deficient in Mecp2 recapitulate many of the symptomatic features of RTT. Recent groundbreaking studies in these mouse models have demonstrated that some symptoms of the disorder, such as general health conditions, defects in mobility, coordination and breathing are reversible. These results raise the question of whether other RTT symptoms, such as impairments in sensory modalities, cognition, social interaction and communication can also be rescued. These features of human behavioral repertoire are all acquired in an experience-dependent manner during well-defined critical periods of plasticity in early postnatal life. As adulthood is reached, neuronal circuits consolidate and plasticity diminishes. To begin to delineate the possibilities and limitations of RTT reversibility, it is necessary to have a better understanding of the underlying mechanism of regression. Neuronal circuits in Mecp2 deficient mice are disrupted and exhibit aberrant excitatory-inhibitory (E/I) balance well before the onset of symptomatic regression. Whether these abnormalities lead to regression is still not clear. Using a sensory circuit model for regression established by the Chen and Fagiolini laboratories, we will address these important questions and test the hypothesis that reversal of sensory circuit defects in Mecp2 KO mice requires the correction of such E/I circuit imbalance. The Chen and Fagiolini Laboratories have independently demonstrated that after initial normal development in Mecp2 KO mice a progressive disruption of thalamic and cortical visual circuits occurs both at the anatomical and functional level. The time course of this regression tracks very closely with onset of RTT phenotypic symptoms. Notably a specific inhibitory circuit, involving the fast-spiking parvalbumin-positive cells (PV), is abnormally connected very early in development prior to the onset of visual function abnormalities and may contribute to silencing of cortical circuits. These results suggest that early abnormalities in the PV inhibitory circuit could drive gradual regression of visual function. PV cells not only regulate critical developmental periods in multiple cortical systems, but also constantly and dynamically adjust brain activity. Here, we will test whether recovery can occur in sensory systems by either globally re-expressing Mecp2 or by manipulating E/I balance selectively in cortex. Taken together, the results of our proposal will provide insight into underlying neuronal circuit dysfunction and regression and, importantly, into novel approaches for treatment.

 描述（由申请人提供）：Rett综合征（RTT）是一种毁灭性的儿科疾病，由MECP 2基因的新生突变引起。Rett综合征诊断的关键特征和基本要求是获得技能的丧失或退化，发生在明显的初始正常发育后的1.5岁和4-5岁之间。一旦退化完成，人们认为这些症状在成年人中是不可逆的。Mecp 2缺陷的小鼠概括了RTT的许多症状特征。最近在这些小鼠模型中进行的突破性研究表明，这种疾病的一些症状，如一般健康状况，活动性，协调性和呼吸缺陷是可逆的。这些结果提出了一个问题，即其他RTT症状，如感觉方式，认知，社会互动和沟通的障碍是否也可以被挽救。人类行为的这些特征都是在出生后早期明确定义的可塑性关键时期以经验依赖的方式获得的。随着成年期的到来，神经元回路得到巩固，可塑性减弱。 为了开始描绘RTT可逆性的可能性和局限性，有必要更好地理解退化的潜在机制。Mecp 2缺陷小鼠的神经元回路被破坏，并在症状消退开始之前表现出异常的兴奋-抑制（E/I）平衡。这些异常是否会导致退化仍不清楚。使用陈和Fagiolini实验室建立的回归感觉回路模型，我们将解决这些重要的问题，并测试Mecp 2 KO小鼠感觉回路缺陷的逆转需要纠正这种E/I回路失衡的假设。 Chen和Fagiolini实验室已经独立地证明，在Mecp 2 KO小鼠的初始正常发育后，在解剖学和功能水平上发生丘脑和皮质视觉回路的进行性破坏。这种回归的时间过程与RTT表型症状的发作非常密切。值得注意的是，一个特定的抑制电路，涉及快速尖峰小白蛋白阳性细胞（PV），异常连接非常早期的发展之前的视觉功能异常的发作，并可能有助于沉默的皮层电路。这些结果表明，PV抑制回路的早期异常可以驱动视觉功能的逐渐退化。PV细胞不仅调节多个皮层系统的关键发育时期，而且还不断动态地调节大脑活动。 在这里，我们将测试恢复是否可以发生在感觉系统中，无论是全球重新表达Mecp 2或通过操纵E/I平衡选择性地在皮层。总之，我们的建议的结果将提供深入了解潜在的神经元回路功能障碍和退化，重要的是，到新的治疗方法。