Regulation of mTOR signaling in the developing cerebral cortex as a point of convergence for multiple autism risk factors

项目摘要/摘要 PTEN和FMR1是自闭症谱系障碍(ASD)的两个易感基因，它们编码 PI3K-Akt-mTOR通路。核糖体蛋白S6(p-S6)的磷酸化是mTOR的下游读数 活动。据报道，自闭症患者死后大脑皮层中的p-s6水平发生了变化。 并在小鼠模型中研究自闭症的危险因素。然而，还不知道在什么时候开发以及在什么时候开发 细胞类型、p-S6信号的失调以及这是否导致ASD的症状。我们的 目标是确定在两个小鼠中p-S6异常调节的常见细胞类型和时间窗口 孤独症危险因素Pten和Fmr1的模型，并研究P-S6调节失调与 社会行为缺陷。我们在这里提出的新假设是，正常情况下富含的细胞类型 因为发育中的大脑中的p-S6选择性地容易受到Pten或Fmr1突变引起的过度生长的影响。 我们建议通过使用一种创新的组合来映射信号的活动来执行这项工作 PI3K-Akt-mTOR/p-S6通路在发育中脑内细胞生长和ASD发病机制中的关键作用 史无前例的时空分辨率、神经解剖追踪和行为表型分析 P-S6调节失调可能在何时何地参与ASD危险因素的病理生理学。此外 为了理解社会行为缺陷的分子和细胞机制，这也将测试 在关键发育时间窗靶向mTOR/p-S6信号转导的治疗潜力 ASD的治疗策略。

PROJECT SUMMARY/ABSTRACT PTEN and FMR1 are two susceptibility genes for autism spectrum disorder (ASD) that encode regulators of the PI3K-Akt-mTOR pathway. Phosphorylation of ribosomal protein S6 (p-S6) is a downstream readout of mTOR activity. Altered levels of p-S6 have been reported in the postmortem cerebral cortex of individuals with autism and in mouse models of autism risk factors. However, it is not known when during development and in which cell types dysregulation of p-S6 signaling occurs and whether this contributes to the symptoms of ASD. Our goal is to identify common cell types and time windows in which p-S6 is dysregulated across two mouse models of autism risk factors, Pten and Fmr1, and to study the relationship between p-S6 dysregulation and social behavioral deficits. The novel hypothesis we develop here is that cell types that are normally enriched for p-S6 in the developing brain are selectively vulnerable to overgrowth caused by Pten or Fmr1 mutations. We propose to carry out this work by using an innovative combination of mapping the activity of a signaling pathway (PI3K-Akt-mTOR/p-S6) key to cellular growth and ASD pathogenesis in the developing brain at unprecedented spatiotemporal resolution, neuroanatomical tracing and behavioral phenotyping to determine when and where dysregulation of p-S6 might contribute to the pathophysiology of ASD risk factors. In addition to understanding molecular and cellular mechanism of social behavioral deficits, this will also test the therapeutic potential of targeting mTOR/p-S6 signaling during a critical developmental time window as a strategy for treating ASD.