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)（21 三体性）的遗传模型，其小鼠 16 号染色体片段与人类 21 号染色体同源。它表现出空间任务学习的异常。与正常二倍体小鼠的海马体相比，该小鼠离体海马体的电生理记录显示出异常的长期增强（LTP）和长期抑制（LTD），这是学习和记忆的模型。体内 1H 磁共振波谱和切除组织的直接化学分析显示，与对照小鼠相比，Ts65Dn 大脑中肌醇水平升高，与人 21 号染色体和鼠 16 号染色体上肌醇转运蛋白基因的位置一致。由于肌醇参与涉及磷脂酶 C 的磷酸肌醇信号传导，因此异常 磷酸肌醇信号传导可能导致 DS 精神发育迟滞，并且可以在这种疾病的小鼠模型中进行检查。三体状况代表膜电活动的广泛功能障碍。在另一种 DS 小鼠模型中，即完全 16 三体小鼠，胎儿舌肌中的全细胞膜片钳证实了活化钾和氯电导的改变。人类：体内 1H 磁共振波谱显示年轻成年 DS 受试者大脑中的肌醇升高，进一步表明异常的磷酸肌醇循环导致 DS 智力低下。老年 DS 受试者（40 岁以上）的脑肌醇进一步升高，其中阿尔茨海默病 (AD) 的神经病理学已得到证实。 由于 AD 本身伴随着高水平的脑肌醇，因此高水平可能被用作遗传上有患病风险但临床上没有痴呆风险的受试者中 AD 的标志。