Rescue of Forebrain Defects in Mouse Models of Down syndrome

描述（由申请人提供）：唐氏综合征（DS），或21三体，是认知障碍的最常见遗传原因，每800名活产婴儿中就有1人受到影响。重要的是，DS中认知障碍的原因尚未发现。我们的小组一直在研究DS的Ts 65 Dn小鼠模型，该模型具有DS中364个三重基因中的184个三重基因。这些小鼠具有大量DS相关表型，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。我们现在报告两个主要的发育前脑表型在Ts 65 Dn之前，这些神经功能缺损：1）背侧前脑异常，导致兴奋性神经元的生产不足和2）腹侧前脑缺陷，导致过度生产抑制性中间神经元。总之，这些缺陷大大改变了Ts 65 Dn中兴奋性：抑制性神经元的比例;我们假设这是Ts 65 Dn/DS中认知功能障碍的主要原因。通过一套全面的细胞增殖，神经分化，基因表达和神经元电生理学的实验，我们发现，两个特定的三重基因（结构相连的转录因子Olig 1和Olig 2）导致腹侧Ts 65 Dn前脑表型，我们拯救了抑制缺陷的胚胎和成人大脑在细胞和电生理水平产生Ts 65 DnOlig 1/2？动物（在Ts 65 Dn背景内将Olig 1和Olig 2基因从3个等位基因减少到2个等位基因）。在此期间的研究中，我们将确定Olig 1/2三倍体是否影响Ts 65 Dn的学习/记忆和突触可塑性缺陷，并研究Dyrk 1a minibrain基因在Ts 65 Dn（背侧）兴奋性神经元缺陷中的作用。 公共卫生相关性：唐氏综合症是最常见的导致智力迟钝的遗传性疾病，约有384，000名美国人（1：800）患有唐氏综合症。因此，开发认知能力疗法对于改善患者及其家属的生活质量至关重要。在这个项目中，我们正在发现哪些三重基因导致Ts 65 Dn唐氏综合征小鼠模型的大脑发育和功能改变。通过减少与早期大脑发育有关的三个三重基因的剂量，这项工作将确定基因靶点，描述它们的过度表达如何改变大脑发育，并导致产前和产后认知治疗策略。

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.