Excitation/inhibition dysbalance in murine and human models of MeCP2 deficiency and Rett syndrome

Rett综合征（RTT）是一种进行性儿童神经发育障碍，主要由编码转录调节因子甲基cpg结合蛋白2 （MeCP2）的x连锁基因的功能缺失突变引起。小鼠MeCP2的缺失导致兴奋性和抑制性神经元功能的改变，表明MeCP2在维持神经回路中精确的兴奋-抑制平衡中起着关键作用。我们的总体目标是阐明RTT中这些神经元的细胞功能障碍和相互作用，重点是BDNF，它是Rett综合征中神经元功能和功能障碍的中枢介质。我们将利用单细胞测序技术直接将单细胞转录组与细胞形态和功能的干扰联系起来。此外，我们计划使用我们实验室最近建立的患者来源的干细胞诱导神经元模型，将小鼠模型的研究移植到人类RTT神经元上。这些方法将显著增强我们在细胞和细胞网络水平上对RTT病理机制的理解，并使我们能够探索假定的治疗靶点，并在RTT中开发更快速的从实验室到患者的方法。

Rett syndrome (RTT) is a progressive childhood neurodevelopmental disorder, resulting predominantly from loss-of-function mutations in the X-linked gene encoding the transcriptional regulator, methyl-CpG binding protein 2 (MeCP2). Loss of murine MeCP2 results in changes in both excitatory and inhibitory neuron function, indicate that MeCP2 plays a pivotal role in maintaining precise excitation-inhibition balance in neural circuits. Our general objective is to elucidate the cellular dysfunction and interaction of these neurons in RTT with a focus on BDNF, which is a central mediator of neuronal function and dysfunction in Rett syndrome. We will utilized single cell sequencing technologies to directly correlate single cell transcriptomes with disturbances in cellular morphology and function. In addition, we plan to port studies from mouse models to human RTT neurons using a patient-derived stem cell-induced neuron model recently established in our lab. These approaches will significantly enhance our understanding of the pathomechanism of RTT at the level of cells and cellular networks, and allow us to explore putative therapeutic targets and develop more rapid bench-to-patient approaches in RTT.