Rescue of Forebrain Defects in Mouse Models of Down syndrome

描述（由申请人提供）：唐氏综合症（DS），或21三体，是最常见的导致认知障碍的遗传原因，每800个活产儿中就有1个患有唐氏综合症。重要的是，导致退行性椎体滑移的认知障碍的原因尚未被发现。我们小组一直在研究DS的Ts65Dn小鼠模型，该模型在DS的364个重复基因中有184个重复。这些小鼠具有大量与DS相关的表型，包括心脏和颅面缺陷以及空间学习/记忆和运动异常，后两者主要在成年动物中测量。我们现在报告了Ts65Dn的两种主要发育性前脑表型，它们先于这些神经缺陷：1)前脑背侧异常，导致兴奋性神经元的产生不足；2)前脑腹侧缺陷，导致抑制性中间神经元的过度产生。总之，这些缺陷实质上改变了Ts65Dn中兴奋性：抑制性神经元的比例；我们假设这是Ts65Dn/DS认知功能障碍的主要原因。通过细胞增殖、神经分化、基因表达和神经元电生理的综合实验，我们发现两个特定的三复制基因（结构相关转录因子Olig1和Olig2）导致腹侧Ts65Dn前脑表型；我们在细胞和电生理水平上通过生成Ts65DnOlig1/2？动物（在Ts65Dn背景下将Olig1和Olig2基因从3个等位基因减少到2个）。在这一阶段的研究中，我们将确定Olig1/2重复是否影响Ts65Dn的学习/记忆和突触可塑性缺陷，并研究Dyrk1a迷你脑基因在Ts65Dn（背侧）兴奋性神经元缺陷中的作用。

DESCRIPTION (provided by applicant): Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive disability, afflicting 1 in every 800 live births. Importantly, the cause(s) of the cognitive disability in DS have not yet been uncovered. Our group has been studying the Ts65Dn mouse model of DS which has triplication of 184 of the 364 genes triplicated in DS. These mice have a large number of DS- relevant phenotypes, including cardiac and craniofacial defects as well as spatial learning/memory and motor abnormalities, the latter two of which have been principally measured in adult animals. We now report two major developmental forebrain phenotypes in Ts65Dn which precede these neurological deficits: 1) a dorsal forebrain abnormality which results in under-production of excitatory neurons and 2) a ventral forebrain defect which results in over-production of inhibitory interneurons. Together, these defects substantially shift the excitatory:inhibitory neuron ratio in Ts65Dn; we hypothesize that this is the primary cause for cognitive dysfunction in Ts65Dn/DS. Through a comprehensive set of experiments on cell proliferation, neural differentiation, gene expression and neuronal electrophysiology, we uncovered that two specific triplicated genes (the structurally linked transcription factors Olig1 and Olig2) cause the ventral Ts65Dn forebrain phenotype; we rescued the inhibitory defect in the embryonic and adult brain at the cellular and electrophysiological levels by generating Ts65DnOlig1/2? animals (reducing Olig1 and Olig2 genes from 3 to 2 alleles within the Ts65Dn background). In this period of study, we will determine whether Olig1/2 triplication influences the learning/memory and synaptic plasticity defects in Ts65Dn and investigate the role of the Dyrk1a minibrain gene in the (dorsal) excitatory neuron deficit in Ts65Dn. PUBLIC HEALTH RELEVANCE: Down syndrome is the most common genetic disorder resulting in mental retardation and it afflicts approximately 384,000 Americans (1:800). As such, the development of therapies for cognitive ability is critical for improving quality of life of patients and their families. In this project, we are discovering which triplicated genes lead to altered brain development and function in the Ts65Dn mouse model of Down syndrome. By reducing the dosage of three triplicated genes implicated in early brain development, this work will identify the gene targets, describe how their over-expression changes brain development and lead to prenatal and postnatal strategies for cognitive therapy.