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

MeCP2 缺陷和 Rett 综合征小鼠和人类模型中的兴奋/抑制失衡

• 批准号: 437833719
• 负责人: Professor Dr. Christian Rosenmund
• 金额: --
• 依托单位: Institut für Neurophysiologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/437833719?language=en
• 关键词: Excitation; inhibition; dysbalance; murine; human

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.

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（MeCP 2）的X连锁基因的功能缺失突变引起。小鼠MeCP 2的缺失导致兴奋性和抑制性神经元功能的变化，表明MeCP 2在维持神经回路中精确的兴奋-抑制平衡中起关键作用。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心介质。我们将利用单细胞测序技术直接关联单细胞转录组与细胞形态和功能的干扰。此外，我们计划使用我们实验室最近建立的患者源性干细胞诱导的神经元模型将研究从小鼠模型移植到人类RTT神经元。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中开发更快速的实验室到患者方法。