Defects in embryonic Neurogenesis and initial synapse formation in the Forebrain of the Ts65Dn mouse model of down syndrome
Defects in embryonic Neurogenesis and initial synapse formation in the Forebrain of the Ts65Dn mouse model of down syndrome
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DOI：
10.1523/jneurosci.3406-07.2007
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发表时间：
2007-10-24
影响因子：
5.3
通讯作者：
Haydar, Tarik F.
中科院分区：
文献类型：
--
作者：
Chakrabarti, Lina;Galdzicki, Zygmunt;Haydar, Tarik F.
21三体是最常见的先天性出生缺陷之一，导致一系列表型，统称为唐氏综合征（DS）。精神发育迟滞和运动和感觉缺陷是DS的许多衰弱症状之一。大脑生长和突触发育的变化被认为是DS认知障碍的基础，但由于缺乏人类胚胎组织以及DS小鼠模型的繁殖困难，早期大脑发育的作用尚未得到研究。我们产生了一个繁殖群体的Ts65Dn小鼠模型的DS测试的假设，即早期缺陷的胚胎脑发育的一个组成部分，脑功能障碍的DS。我们发现，由于细胞周期持续时间较长，脑室区神经前体细胞的神经发生减少，Ts65Dn大脑皮层和海马的产前生长出现了实质性延迟。此外，Ts65Dn新皮质在出生后仍然是细胞减少的，并且在出生后第一周开始突触发育持续减少。这些结果表明，特定的异常胚胎前脑前体细胞之前的早期缺陷，突触和可能的基础出生后残疾的Ts65Dn和DS。因此，产前早期是一个重要的新窗口，可能治疗改善认知症状的DS。
Trisomy 21, one of the most prevalent congenital birth defects, results in a constellation of phenotypes collectively termed Down syndrome (DS). Mental retardation and motor and sensory deficits are among the many debilitating symptoms of DS. Alterations in brain growth and synaptic development are thought to underlie the cognitive impairments in DS, but the role of early brain development has not been studied because of the lack of embryonichuman tissue and because of breeding difficulties in mouse models of DS. We generated a breeding colony of the Ts65Dn mouse model of DS to test the hypothesis that early defects in embryonic brain development are a component of brain dysfunction in DS. We found substantial delays in prenatal growth of the Ts65Dn cerebral cortex and hippocampus because of longer cell cycle duration and reduced neurogenesis from the ventricular zone neural precursor population. In addition, the Ts65Dn neocortex remains hypocellular after birth and there is a lasting decrease in synaptic development beginning in the first postnatal week. These results demonstrate that specific abnormalities in embryonic forebrain precursor cells precede early deficits in synaptogenesis and may underlie the postnatal disabilities in Ts65Dn and DS. The early prenatal period is therefore an important new window for possible therapeutic amelioration of the cognitive symptoms in DS.