Effects of neural progenitor cell transplantation in neonatal Ts65Dn mice.

描述(申请人提供)：21号染色体的三倍体导致唐氏综合征(DS)儿童智力发育迟缓。尽管大脑在出生时受到一定程度的损害，但与DS相关的大部分异常发育发生在出生后发育中的结构中，如海马体。事实上，患有DS的儿童在海马体介导的空间任务上有特别的困难。除了童年学习延迟外，患有DS的人还受到早期阿尔茨海默病的额外认知压力。之前在胎儿致死性16DS三体小鼠模型中的工作表明，TS16-二倍体嵌合体小鼠的二倍体细胞可以预防致死性，嵌合体小鼠存活长达一年。神经前体细胞(NPC)已被用于治疗具有全球性病理的疾病，如DS所见。鼻咽癌可以迁移、分化为神经胶质细胞和神经元，并分泌生长因子促进内源性神经元存活，为内源性神经元提供指导信号。这导致了一种假设，即鼻咽癌可能是一种非常有用的早期治疗DS的方法，并在关键的早期学习期间模拟更正常的神经解剖发育。这项拟议的纵向研究将检验鼻咽癌移植对DS小鼠模型Ts65Dn小鼠认知和神经解剖学的影响。目的1：探讨小鼠鼻咽癌(MNPC)海马区移植对Ts65Dn小鼠早期和晚期认知功能障碍的影响。出生后第2天的小鼠将被双侧植入C17.2 mNPC到海马区。行为测试将在2个月、6个月和12个月时评估认知功能。三种不同的行为测试将被用来得出学习和记忆途径的特定组成部分的功能。目的2：确定mNPC的存活水平及其在移植小鼠一生中的命运。在每一轮行为测试之后，将对一组动物进行免疫组织化学分析。将评估mNPC的存活、迁移和分化，预计与学习和记忆有关的区域(海马体、内侧隔和前额叶皮质)mNPC浓度较高。目的：研究大鼠海马区和前额叶皮质突触前密度和树突形态的变化。用高尔基体染色和突触素免疫组织化学分别检测树突形态和突触前密度。目标2和目标3的结果将与目标1中的行为研究相关联。公共卫生相关性：早期使用NPC可能能够提高认知功能，使患有DS的儿童更容易学习。此外，允许大脑进行正确的初始连接可能会防止唐氏综合症患者面临的阿尔茨海默病的早期发病。

DESCRIPTION (provided by applicant): The triplication of chromosome 21 results in mental retardation for children with Down syndrome (DS). Although the brain is somewhat compromised at birth, much of the abnormal development associated with DS occurs in postnatal developing structures, such as the hippocampus. Indeed, children with DS have particular difficulty with hippocampal-mediated spatial tasks. In addition to childhood learning delays, individuals with DS are subjected to the additional cognitive stress of early Alzheimer's disease. Previous work in the fetal lethal Trisomy 16 DS mouse model demonstrated diploid cells in Ts16-diploid chimeric mice prevent the lethality and the chimeric mice survive up to one year. Neural progenitor cells (NPC) have been used to treat diseases with a global pathology, as is seen in DS. NPC can migrate, differentiate into glia and neurons, and secrete growth factors to promote the survival of and provide guidance cues for endogenous neurons. This has lead to the hypothesis that NPC may be useful as a very early treatment of DS and model a more normal neuro-anatomical development during the critical early learning period. The proposed longitudinal study will examine the effects of NPC transplantation on cognition and neuroanatomy in the DS mouse model, the Ts65Dn mouse. Aim 1: Determine if murine NPC (mNPC) transplanted into the hippocampus can alleviate the early and late cognitive dysfunction in Ts65Dn mice. Postnatal day 2 mice will be bilaterally implanted with C17.2 mNPC into the hippocampus. Behavior testing will assess cognitive function at 2, 6, and 12 months of age. Three different behavior tests will be employed to elicit the function of specific components of the learning and memory pathway. Aim 2: Determine the level of mNPC survival and their fate over the lifetime of the transplanted mice. A subset of animals will be analyzed immunohisto- chemically after each round of behavior testing. mNPC survival, migration, and differentiation will be assessed, with higher mNPC concentrations expected in areas involved in learning and memory (the hippocampus, medial septum, and prelimbic prefrontal cortex). Aim 3: Investigate alterations in presynaptic densities and dendritic morphology in the hippocampus and prefrontal cortex. Golgi staining and immuno- histochemistry against synaptophysin will be used to examine dendritic morphology and presynaptic density, respectively. Results from Aims 2 and 3 will be correlated with behavioral research obtained in Aim 1. Public Health Relevance: The use of NPC at an early age may be able to increase cognitive function and make learning easier for children with DS. Furthermore, allowing the brain to make the correct initial connections may prevent the early onset of Alzheimer's disease that people with Down syndrome face.