Visual Circuit Regression and its Rescue in RTT Mouse Models

 描述(申请人提供)：Rett综合征(RTT)是一种毁灭性的儿科疾病，由MECP2基因的从头突变引起。Rett综合征诊断的主要特征和基本要求是获得性技能的丧失或退化，发生在1.5岁到4-5岁之间，在明显的正常发育之后。一旦消退完成，人们认为成年人的症状是不可逆转的。缺乏MeCP2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开创性研究表明，这种疾病的一些症状是可逆的，如一般健康状况、活动、协调和呼吸方面的缺陷。这些结果提出了一个问题，即RTT的其他症状，如感觉通道、认知、社交和交流方面的障碍是否也可以挽救。人类行为体系的这些特征都是在出生后早期生活中明确定义的可塑性关键时期以经验依赖的方式获得的。随着成年的到来，神经元回路巩固，可塑性减弱。为了开始描述RTT可逆性的可能性和局限性，有必要更好地理解回归的潜在机制。MeCP2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倒退仍不清楚。使用Chen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问题，并检验以下假设：MeCP2 KO小鼠感觉回路缺陷的逆转需要纠正这种E/I回路失衡。Chen和Fagiolini实验室已经独立证明，MeCP2 KO小鼠在最初正常发育后，在解剖和功能水平上都会出现丘脑和皮质视觉回路的进行性中断。这种回归的时间进程与RTT表型症状的发生密切相关。值得注意的是，涉及快速放电的小白蛋白阳性细胞(PV)的特定抑制电路在视觉功能异常开始之前的发育早期就异常连接，可能有助于大脑皮质电路的沉默。这些结果表明，PV抑制回路的早期异常可能导致视觉功能的逐渐退化。光伏细胞不仅调节多个皮质系统中的关键发育期，而且不断地和动态地调节大脑活动。在这里，我们将测试是否可以通过全局重新表达MeCP2或通过有选择地操纵皮层的E/I平衡来在感觉系统中发生恢复。综上所述，我们的建议的结果将为深入了解潜在的神经元回路功能障碍和退化，以及重要的是，对新的治疗方法提供洞察。

 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.