Respiratory Circuit Dysfunction in Rett Syndrome

描述(申请人提供)：Rett综合征(RTT)是一种复杂的自闭症谱系障碍(ASD)，由MECP2基因突变引起，影响全球约10,000名活产女婴中的1名。除了认知、运动和行为缺陷外，RTT最严重的身体衰弱后果之一是呼吸控制严重中断，高达25%的RTT患者可能因心肺并发症而过早死亡。目前，RTT中还没有针对呼吸障碍或任何其他神经缺陷的治疗方法。我们对RTT呼吸功能障碍的神经机制的理解受到以下事实的阻碍：我们仍然对MECP2的缺失如何影响特定脑干呼吸回路中的神经元和/或突触功能知之甚少。因此，这项拟议的研究采用了多学科的方法来定义MECP2的基因缺失如何扰乱呼吸控制，重点是使用明确定义的疾病小鼠模型来调节脑干关键呼吸反射通路中的兴奋-抑制平衡。电生理学方法将用于体外脑干切片，以检验初级传入突触兴奋性增加，调节对低氧和肺充气的反射反应，导致RTT呼吸回路功能障碍的假说，并确定潜在的机制。我们还将研究脑源性神经营养因子(BDNF)的缺陷是如何导致突触功能障碍的，以及增强BDNF信号的分子在体外和体内恢复RTT小鼠正常功能的能力。脑源性神经营养因子是一种关键的神经信号分子，其表达在RTT中严重下降。此外，我们将使用Fos免疫染色来绘制整个脑干呼吸网络中神经元和/或突触功能在体内被破坏的位置。最后，我们将研究人类BDNF基因的常见多态Val66Met-BDNF如何影响小鼠呼吸道症状的严重性和对BDNF靶向治疗的治疗反应。这项拟议的研究旨在通过创新的实验方法和小鼠模型来确定RTT呼吸功能障碍的基础机制。通过专注于突触兴奋性，特别是BDNF介导的信号传递，希望这些研究将促进RTT呼吸障碍的新治疗策略的发展。此外，希望从RTT中对回路功能障碍的分析中获得的见解将广泛适用于ASD作为一个整体。 公共卫生相关性：拟议的研究试图定义Rett综合征(RTT)呼吸障碍的基础机制，RTT是一种毁灭性的自闭症谱系障碍，影响全球约10,000名女婴中的1例。RTT患者患有无法控制的过度换气和屏气，高达25%的患者过早死于心肺并发症。拟议的研究将使用RTT的小鼠模型来识别导致这种疾病中异常呼吸的神经细胞功能缺陷，并开发潜在的新治疗方法。

DESCRIPTION (provided by applicant): Rett syndrome (RTT) is a complex Autism Spectrum Disorder (ASD) that is caused by mutations in the MECP2 gene and affects approximately 1 in 10,000 live female births worldwide. In addition to cognitive, motor and behavioral deficits, one of the most physically debilitating consequences of RTT is severe disruption in the control of breathing, and up to 25% of RTT patients may die prematurely of cardiorespiratory complications. Currently, there are no treatments available for breathing disorders, or any other neurologic deficits in RTT. Our understanding of neural mechanisms that underlie respiratory dysfunction in RTT is hampered by the fact that we still know little about how loss of MECP2 affects neuronal and/or synaptic function in specific brainstem respiratory circuits. Therefore, the proposed research takes a multidisciplinary approach to define how genetic loss of MECP2 disrupts respiratory control, focusing on modulation of excitatory-inhibitory balance in key respiratory reflex pathways in the brainstem using a well-defined mouse model of the disease. Electrophysiological methods will be used in brainstem slices in vitro to test the hypothesis that increased excitability at primary afferent synapses regulating reflex responses to hypoxia and lung inflation contributes to respiratory circuit dysfunction in RTT and to define underlying mechanisms. We will also examine how deficits in Brain Derived Neurotrophic Factor (BDNF), a key neuronal signaling molecule whose expression is severely decreased in RTT, contribute to synaptic dysfunction, as well as the ability of molecules that enhance BDNF signaling to restore normal function in RTT mice in vitro and in vivo. In addition, we will use Fos immunostaining to map sites throughout the brainstem respiratory network at which neuronal and/or synaptic function is disrupted in vivo. Finally, we will examine how a common polymorphism in the human BDNF gene, Val66Met-BDNF, influences the severity of respiratory symptoms and the therapeutic response to BDNF- targeted therapies in mice. The proposed research aims to define mechanisms that underlie respiratory dysfunction in RTT using innovative experimental approaches and mouse models. By focusing on synaptic excitability, and BDNF-mediated signaling in particular, it is hoped these studies will foster development of new therapeutic strategies for breathing disorders in RTT. Moreover, it is hoped that insights obtained from analysis of circuit dysfunction in RTT will be broadly applicable to ASDs as a whole. PUBLIC HEALTH RELEVANCE: The proposed research seeks to define mechanisms that underlie breathing disorders in Rett syndrome (RTT), a devastating Autism Spectrum Disorder affecting approximately 1 in 10,000 female births worldwide. RTT patients suffer from uncontrollable periods of hyperventilation and breath-holding and up to 25% die prematurely of cardiorespiratory complications. The proposed studies will use mouse models of RTT to identify defects in nerve cell function that cause abnormal breathing in this disease and to develop potential new therapeutic approaches.