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唐氏综合征（DS）儿童的智力迟钝。虽然大脑在出生时有些受损，但与DS相关的许多异常发育发生在出生后发育的结构中，如海马。事实上，患有DS的儿童在完成以露营为媒介的空间任务时特别困难。除了儿童期学习延迟外，患有DS的个体还受到早期阿尔茨海默病的额外认知压力。先前在胎儿致死性三体16 DS小鼠模型中的工作证明了Ts16-二倍体嵌合小鼠中的二倍体细胞防止致死性，并且嵌合小鼠存活长达一年。神经祖细胞（NPC）已被用于治疗具有全球病理学的疾病，如在DS中所见。NPC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的存活，为内源性神经元提供导向线索。这导致了一种假设，即NPC可能是有用的，作为一个非常早期的治疗DS和模型更正常的神经解剖发展在关键的早期学习期。拟议的纵向研究将检查NPC移植对DS小鼠模型Ts65Dn小鼠的认知和神经解剖学的影响。目的1：研究小鼠鼻咽癌（mNPC）海马移植对Ts65Dn小鼠早期和晚期认知功能障碍的影响。出生后第2天的小鼠将双侧植入C17.2 mNPC到海马中。行为测试将评估2个月、6个月和12个月大时的认知功能。将采用三种不同的行为测试来引出学习和记忆途径的特定组件的功能。目的2：确定mNPC存活水平及其在移植小鼠一生中的命运。在每轮行为试验后，对一个动物亚组进行免疫组织化学分析。将评估mNPC存活、迁移和分化，预期在参与学习和记忆的区域（海马、内侧隔和前边缘前额叶皮质）中mNPC浓度较高。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。高尔基体染色和突触素免疫组化分别用于检查树突形态和突触前密度。目标2和3的结果将与目标1中获得的行为研究相关。公共卫生相关性：早期使用NPC可能能够增加认知功能，使DS儿童更容易学习。此外，允许大脑进行正确的初始连接可以防止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.