Effects of neural progenitor cell transplantation in neonatal Ts65Dn mice.

描述（由申请人提供）：21号染色体的三倍导致患有唐氏综合症（DS）的儿童智力迟钝。虽然大脑在出生时有些受损，但与退行性椎体滑移相关的大部分异常发育发生在出生后的发育结构中，如海马体。事实上，患有退行性痴呆的儿童在完成海马体介导的空间任务方面尤其困难。除了儿童学习迟缓，退行性痴呆患者还会受到早期阿尔茨海默病的额外认知压力。先前对胎儿致死性16三体DS小鼠模型的研究表明，ts16 -二倍体嵌合小鼠体内的二倍体细胞可防止致死性，嵌合小鼠可存活长达一年。神经祖细胞（NPC）已被用于治疗具有全局病理的疾病，如在退行性椎体滑移中所见。NPC可以迁移，分化为胶质细胞和神经元，并分泌生长因子促进内源性神经元的存活，为内源性神经元提供引导信号。这导致假设鼻咽癌可能是非常有用的早期治疗退行性椎体滑移和模型更正常的神经解剖发育在关键的早期学习时期。这项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：确定小鼠NPC （mNPC）海马移植是否能缓解Ts65Dn小鼠早期和晚期认知功能障碍。将出生第2天的小鼠双侧海马内植入C17.2 mNPC。行为测试将评估2、6和12个月大时的认知功能。三种不同的行为测试将被用来引出学习和记忆通路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。在每一轮行为测试后，将对一部分动物进行免疫组化分析。将评估mNPC的存活、迁移和分化，预计在涉及学习和记忆的区域（海马体、中隔和前边缘前额皮质）会有更高的mNPC浓度。目的3：研究海马和前额皮质突触前密度和树突形态的变化。高尔基染色法和免疫组化法分别用于检查树突形态和突触前密度。Aims 2和3的结果将与Aim 1中获得的行为研究相关联。公共卫生相关性：早期使用鼻咽癌可能能够提高退行性椎体滑移儿童的认知功能，使其更容易学习。此外，允许大脑做出正确的初始连接可能会预防唐氏综合症患者面临的阿尔茨海默病的早期发作。

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.