Circuit-based therapy for rett syndrome

描述(申请人提供)：神经发育障碍的第一个症状，如Rett综合征，出现在童年早期，当时感觉经验正在塑造成熟大脑中的神经元回路6。MeCP2基因突变占RTT病例的80%。MeCP2调节一系列基因的表达，并根据分子和/或细胞环境协调转录抑制或激活。这直接暗示了神经发育障碍的表观遗传途径。有趣的是，MeCP2表达的扰动改变了皮层兴奋性/抑制性的动态平衡，有利于视觉皮层的抑制18。此外，感觉体验可以选择性地诱导MeCP2磷酸化，调节树突图案、脊椎形态发生和BDNF转录101。令人惊讶的是，可以通过延迟修复MeCP2基因31、32、54以及过度表达BDNF9来挽救RTT样神经缺陷。通过在小鼠身上建立可逆性原理，这些研究表明RTT和相关的疾病也是可逆的，即使在疾病的晚期也是如此。我们的研究表明，兴奋性/抑制性平衡决定了视觉皮质成熟的关键期的时间。直接操纵这种平衡可以加速或延迟依赖活动的过程，并可以成功地用于挽救可塑性缺陷23-25，46，47。扰乱神经元活动会导致基因表达模式的异常，其中许多与错误调控的表观遗传系统有关。我们的中心假设是，在婴儿大脑皮质可塑性增强的关键时期，兴奋/抑制平衡以一种活性依赖的方式驱动MeCP2对基因翻译和抑制的调节。它们的破坏导致了复杂的神经发育障碍的行为表型，如Rett综合征。因此，兴奋性/抑制性平衡的操纵将被用来挽救Rett综合征动物模型的皮质损伤。通过应用体内电生理技术，我们旨在揭示MeCP2功能在皮层回路精化过程中兴奋/抑制回路平衡中的作用。这一结果将为神经发育障碍患者重新激活大脑可塑性提供潜在的治疗策略。公共卫生相关性：在目前的拨款中，我们建议测试这一假设，即在婴儿期皮质可塑性增强的关键时期，兴奋/抑制平衡以一种依赖于活动的方式驱动基因翻译和抑制的复杂表观遗传状态。它们的破坏导致了神经发育障碍的复杂行为表型，如Rett综合征和自闭症。通过应用体内电生理技术，我们旨在揭示MeCP2在皮层回路精化中与兴奋/抑制回路平衡有关的功能。这一结果将为恢复Rett综合征动物模型的脑可塑性提供潜在的治疗策略。

DESCRIPTION (provided by applicant): The first symptoms of neurodevelopmental disorder such as Rett Syndrome appear during early childhood when sensory experience is sculpting neuronal circuits in what it will become the mature brain6. Mutations in MeCP2 gene account for 80% of RTT cases. MeCP2 regulates the expression of a wide range of genes and can coordinate either transcriptional repression or activation depending on the molecular and/or cellular context. This directly implicates an epigenetic pathway in neurodevelopmental disorders. Interestingly, perturbation of MeCP2 expression shifts the dynamic cortical excitatory/inhibitory balance in favor of inhibition in visual cortex18. Moreover, sensory experience can selectively induce MeCP2 phosphorylation, regulating dendritic patterning, spine morphogenesis, and BDNF transcription101. Surprisingly, RTT-like neurological defects can be rescued by delayed restoration of MeCP2 gene31,32,54 as well as overexpression of BDNF9. By establishing the principle of reversibility in mice, these studies suggest that RTT and related disorders are also reversible, even in the late stages of the disease. Our research has revealed that excitatory/inhibitory balance dictates the timing of critical periods of visual cortical maturation23. Direct manipulation of this balance can accelerate or delayed activity-dependent processes and can be used successfully to rescue plasticity defects23-25,46,47 . Perturbing neuronal activity causes aberrant gene-expression patterns, many of which are linked to misregulated epigenetic systems. Our central hypothesis is that the excitatory/inhibitory balance drives MeCP2 regulation of gene translation and repression in an activity-dependent manner during critical periods of heightened cortical plasticity in infancy. Their disruption leads to the complex behavioral phenotype of neurodevelopmental disorders such as Rett Syndrome. Hence, manipulation of Excitatory/Inhibitory balance will be used to rescue cortical impairments in animal models of Rett syndrome. By applying in vivo electrophysiological techniques, we aim to reveal role of MeCP2 function in excitatory/inhibitory circuit balance during cortical circuit refinement. The results will provide potential therapeutic strategies for reactivating brain plasticity in neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: In the present grant, we propose to test the hypothesis that an excitatory/inhibitory balance drives a complex epigenetic state of gene translation and repression in an activity-dependent manner during critical periods of heightened cortical plasticity in infancy. Their disruption leads to the complex behavioral phenotype of neurodevelopmental disorders such as Rett Syndrome and ASDs. By applying in vivo electrophysiological techniques, we aim to reveal MeCP2 function in relation to excitatory/inhibitory circuit balance in cortical circuit refinement. The results will provide potential therapeutic strategies for reactivating brain plasticity in animal models of Rett Syndrome.