DOWN SYNDROME, NEURODEVELOPMENT & NEURODEGENERATION

唐氏综合症、神经发育

• 批准号: 6434775
• 负责人: Stanley I. Rapoport
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6434775
• 关键词: Downs syndrome; calcium channel; cell biology; disease /disorder model; hippocampus; human tissue; laboratory mouse; neurons; neuropharmacology; polymerase chain reaction; potassium channel; saxitoxin; sodium channel; tissue /cell culture; voltage gated channel

Animal Model: The Ts65Dn mouse, a genetic model of human Down syndrome (DS) (trisomy 21), is trisomic for the segment of murine chromosome 16 that is homologous to human chromosome 21. It demonstrates abnormal learning of spatial tasks. Electrophysiological recording from the isolated hippocampus from this mouse demonstrated abnormal long-term potentiation (LTP) and long term depression (LTD), models for learning and memory, compared with the hippocampus from normal diploid mice. In vivo 1H magnetic resonance spectroscopy and direct chemical analysis of excised tissue showed an increased level of myoinositol in brains of Ts65Dn compared with control mice, consistent with the location of the myoinositol transporter gene on human chromosome 21 and murine chromosome 16. As myoinositol participates in phosphoinositide signaling involving phospholipase C, abnormal phosphoinositide signaling may contribute to mental retardation in DS, and can be examined in a mouse model of this disorder. The trisomic condition represents widespread dysfunction of membrane electrical activity. In another mouse model of DS, the full trisomy 16 mouse, altered activated potassium and chloride conductances were demonstrated by whole cell patch clamp in fetal tongue muscle. Humans: In vivo 1H magnetic resonance spectroscopy demonstrated elevated myoinositol in the brain of young adult DS subjects, further suggesting that an abnormal phosphoinositide cycle contributes to mental retardation in DS. Brain myoinositol was further elevated in older DS subjects (more than 40 years), in which Alzheimer disease (AD) neuropathology has been demonstrated. As AD itself is accompanied by high brain myoinositol, a high level might be used as a marker of AD in subjects genetically at risk for disease but not clinically demented.

动物模型：TS65DN小鼠是人类唐氏综合症（DS）的遗传模型（三体疾病），是鼠类16染色体片段的三体，它与人类染色体同源于21。与正常二倍体小鼠的海马相比，从该小鼠分离的海马的电生理记录表现出异常的长期增强（LTP）和长期抑郁（LTD），学习和记忆模型。与对照小鼠相比，切除组织的体内1H磁共振光谱和直接化学分析在TS65DN的大脑中表现出增加的肌酸水平，与对照组的肌酸转运蛋白转运蛋白基因的位置一致，在21号人类染色体上的位置和鼠类16的人体染色体，肌酸参与肌脱磷酸磷酸化的磷酸化含量。磷酸肌醇信号传导可能会导致DS的智力低下，并且可以在该疾病的小鼠模型中检查。三化条件代表膜电活动的广泛功能障碍。在另一种DS的小鼠模型中，全细胞贴夹在胎舌肌肉中证明了活化的钾和氯化物电导的改变。人类：体内1H磁共振光谱表明，年轻成人DS受试者的大脑中肌醇升高，进一步表明异常的磷酸肌醇周期有助于DS的智力低下。在较旧的DS受试者（超过40年）中，大脑肌无辛醇进一步升高，其中已经证明了阿尔茨海默氏病（AD）神经病理学。 由于AD本身伴随着高脑肌醇的伴随，因此在遗传上有疾病风险的受试者中，高水平可能被用作AD的标志，但没有临床痴呆。