Rescue of Forebrain Defects in Mouse Models of Down syndrome

唐氏综合症小鼠模型前脑缺陷的挽救

• 批准号: 8214387
• 负责人: ZYGMUNT GALDZICKI
• 金额: $ 44.97万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214387
• 关键词: Action Potentials; Adult; Alleles; American; Animals; Axon; Behavioral; Brain; Cardiac; Cell Differentiation process; Cell Proliferation; Cognitive; Cognitive Therapy; Data; Defect; Demyelinations; Development; Dorsal; Down Syndrome; Electrophysiology (science); Embryo; Family; Funding; Gene Dosage; Gene Expression; Gene Targeting; Genes; Genetic; Hereditary Disease; Hippocampus (Brain); Human; Impaired cognition; Interneurons; Lead; Learning; Life; Link; Live Birth; Long-Term Potentiation; Measures; Mediating; Memory; Mental Depression; Mental Retardation; Motor; Mus; Myelin; Neurologic; Neurologic Dysfunctions; Neurons; Oligodendroglia; Patients; Phenotype; Production; Prosencephalon; Quality of life; Reporting; Role; Running; Synaptic plasticity; Testing; Therapeutic; Time; Ventricular; Work; alertness; craniofacial; disability; dosage; excitatory neuron; functional disability; hippocampal pyramidal neuron; improved; in vivo; inhibitory neuron; mature animal; morris water maze; mouse Ts65Dn; mouse model; multidisciplinary; nerve stem cell; neurobehavior; neurogenesis; oligodendrocyte precursor; postnatal; precursor cell; prenatal; relating to nervous system; research study; therapy development; transcription factor

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.

描述（由申请人提供）：唐氏综合症（DS）或第21三体综合征是认知障碍的最常见遗传原因，每800个活产中会遭受1个。重要的是，尚未发现DS认知障碍的原因。我们的小组一直在研究DS的TS65DN小鼠模型，该模型在DS中三率的364个基因中的184个三重置。这些小鼠具有大量相关的表型，包括心脏和颅面缺陷以及空间学习/记忆和运动异常，后两种主要是在成年动物中测量的。现在，我们报告了TS65DN中的两个主要发育前脑表型，该表型先于这些神经功能缺陷：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量产生抑制性脑膜元。总之，这些缺陷大大改变了兴奋性：TS65DN中的抑制性神经元比；我们假设这是TS65DN/DS中认知功能障碍的主要原因。通过一系列有关细胞增殖，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三重基因（结构连接的转录因子OLIG1和OLIG2）导致腹侧TS65DN前脑表型。我们通过产生TS65DNOLIG1/2来营救细胞和电生理水平的胚胎和成人大脑中的抑制性缺陷？动物（在TS65DN背景下将Olig1和Olig2基因从3个等位基因降低到2个等位基因）。在这段研究期间，我们将确定Olig1/2一式固定是否影响TS65DN中的学习/记忆和突触可塑性缺陷，并研究DYRK1A Minibrain基因在TS65DN中（背侧）兴奋性神经元缺陷中的作用。 公共卫生相关性：唐氏综合症是导致智力低下的最常见遗传疾病，它折磨了约384,000名美国人（1：800）。因此，认知能力的疗法的发展对于改善患者及其家人的生活质量至关重要。在这个项目中，我们发现哪种一式三份基因会导致唐氏综合症TS65DN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式三份基因的剂量，这项工作将确定基因靶标，描述它们的过表达如何改变脑发育，并导致认知疗法的产前和产后策略。