Rescue of Forebrain Defects in Mouse Models of Down syndrome

描述(申请人提供)：唐氏综合症(DS)，或21三体，是导致认知障碍的最常见的遗传原因，每800名活产儿中就有1名患有此病。重要的是，DS患者认知障碍的原因(S)尚未被发现。我们小组一直在研究DS的Ts65Dn小鼠模型，在DS中的364个基因中，有184个基因是三倍的。这些小鼠具有大量与DS相关的表型，包括心脏和颅面部缺陷以及空间学习/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在这些神经缺陷之前的两种主要发育前脑表型：1)背侧前脑异常，导致兴奋性神经元产生不足；2)腹侧前脑缺陷，导致抑制性中间神经元过度产生。总之，这些缺陷大大改变了Ts65Dn的兴奋性神经元与抑制性神经元的比率；我们假设这是Ts65Dn/DS认知功能障碍的主要原因。通过对细胞增殖、神经分化、基因表达和神经元电生理的一系列实验，我们发现Ts65Dn腹侧前脑表型是由两个特殊的三重基因(结构上连锁的转录因子Opol1和Olob2)引起的，我们通过产生Ts65DnOpol1/2？动物(在Ts65Dn背景下，将寡核苷酸1和寡核苷酸2基因从3个等位基因减少到2个等位基因)。在这一研究中，我们将确定1/2三重复制是否影响Ts65Dn的学习/记忆和突触可塑性缺陷，并探讨Dyrk1a微脑基因在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.