Respiratory Circuit Dysfunction in Rett Syndrome

描述（由申请人提供）：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，全球每10,000名活产女性中约有1名受到影响。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患者可能过早死于心肺并发症。目前，对于RTT中的呼吸障碍或任何其他神经系统缺陷，还没有可用的治疗方法。我们对RTT呼吸功能障碍背后的神经机制的理解受到阻碍，因为我们仍然对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，本研究采用多学科方法来确定MECP2基因缺失如何破坏呼吸控制，重点关注脑干关键呼吸反射通路中兴奋-抑制平衡的调节，并使用定义良好的疾病小鼠模型。电生理方法将用于体外脑干切片，以验证RTT中调节缺氧和肺膨胀反射反应的初级传入突触兴奋性增加导致呼吸回路功能障碍的假设，并确定其潜在机制。我们还将研究脑源性神经营养因子（BDNF）的缺陷如何导致突触功能障碍，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。BDNF是一种关键的神经元信号分子，在RTT中表达严重减少。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部位。最后，我们将研究人类BDNF基因Val66Met-BDNF的常见多态性如何影响呼吸系统症状的严重程度以及小鼠对BDNF靶向治疗的治疗反应。该研究旨在通过创新的实验方法和小鼠模型来确定RTT呼吸功能障碍的机制。通过关注突触兴奋性，特别是bdnf介导的信号传导，希望这些研究将促进RTT呼吸障碍新治疗策略的发展。此外，希望从RTT的电路功能障碍分析中获得的见解将广泛适用于整个asd。

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.