DOWN SYNDROME, NEURODEVELOPMENT & NEURODEGENERATION

动物模型：Ts65Dn小鼠是人类唐氏综合症(DS)(21三体)的遗传模型，是与人类21号染色体同源的小鼠16号染色体片段的三体。它显示了空间任务的异常学习。与正常二倍体小鼠的海马体相比，这只小鼠分离的海马区的电生理记录显示出学习和记忆的异常长时程增强(LTP)和长时程抑制(LTD)模型。体内1H磁共振波谱和切除组织的直接化学分析显示，与对照组小鼠相比，Ts65Dn小鼠脑内肌醇水平增加，这与肌醇转运蛋白基因在人类21号染色体和小鼠16号染色体上的位置一致。由于肌醇参与了涉及磷脂酶C的磷脂酰肌醇信号转导，异常的肌醇信号可能导致DS患者的智力低下，并可在这种疾病的小鼠模型中检测到。三体状态表现为广泛的膜电活动障碍。在另一种DS小鼠模型中，胎儿舌肌全三体16小鼠的全细胞膜片钳显示其激活的钾和氯电导发生改变。人类：活体1H磁共振波谱显示年轻成年DS受试者大脑中肌醇升高，进一步表明异常的磷脂酰肌醇循环与DS的智力低下有关。在老年DS患者(超过40岁)中，脑肌醇进一步升高，其中阿尔茨海默病(AD)的神经病理已被证实。由于阿尔茨海默病本身伴有高水平的脑肌醇，高水平可能被用来作为具有疾病遗传风险但临床上没有痴呆的受试者的AD的标志。

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.