Human cortical development and neural plasticity altered by trisomy 21

摘要 唐氏综合征（DS，21三体，T21）是一种复杂的多基因疾病，也是最常见的遗传原因， 智力残疾。然而，令人惊讶的是，人们对导致认知障碍的潜在机制知之甚少。 在DS中受损。成年DS皮质神经元较少，神经发生和突触发生减少 被认为是DS发展的特征。然而，特定的神经元和突触接触 在发育的哪个阶段受到影响，以及导致这些缺陷的分子途径是什么 智力残疾情况仍不清楚。我们建议建立基于人类诱导多能干细胞的模型 （iPSCs），以询问T21如何破坏DS的发育过程。为了确保干细胞的有效性 基于模型，我们将首先建立一个细胞，突触和分子图谱的DS产前皮质。通过 将单细胞的分子特征与体内和体外模型中的细胞变化相结合， 将梳理出被T21破坏的分子通路，这些分子通路解释了神经发育的改变。 这些实验的结果将提供对DS中智力残疾的机械理解。更 总的来说，这些结果将解决我们对人类皮层神经元发育的理解中的差距， 错误的后果。

ABSTRACT Down syndrome (DS, trisomy 21, T21), a complex multigene disorder and the most common genetic cause of intellectual disability. However, surprisingly little is known about the underlying mechanisms that lead to cognitive impairment in DS. There are fewer neurons in adult DS cortex and reduced neurogenesis and synaptogenesis have been implicated as features of DS development. Yet, what and how specific neurons and synaptic contacts are affected at which period of development and what molecular pathways underlie these defects that lead to intellectual disability remain unclear. We propose to build models based on human induced pluripotent stem cells (iPSCs), to interrogate how T21 disrupts developmental processes in DS. To ensure the validity of the stem cell based models, we will first establish a cellular, synaptic, and molecular atlas of the DS prenatal cortex. By integrating molecular signatures of single cells with the cellular changes both in vivo and in in vitro models, we will tease out the molecular pathways that are disrupted by T21 that account for the altered neural development. The results from these experiments will provide mechanistic understanding of intellectual disability in DS. More broadly, the results will address gaps in our understanding of human cortical neuron development and consequences of mistakes.