CELL BIOLOGY OF MODELS FOR HUMAN BRAIN DISORDERS

人脑疾病模型的细胞生物学

• 批准号: 6288685
• 负责人: ZYGMUNT GALDZICKI
• 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/6288685
• 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

The segmental trisomy mouse (Ts65Dn) is an animal model of human Down syndrome (trisomy 21). It is trisomic only for the segment of chromosome 16 that is homologous to human chromosome 21. The adult Ts65Dn mouse demonstrates abnormal learning on spatial tasks. We found that the isolated hippocampus from this mouse also demonstrates abnormal long-term potentiation (LTP) and long term depression (LTD), models for learning and memory. Expression of the NMDA receptor main subunit (NR1) and of the alpha-1C Ca2+ channel subunit proteins, estimated by Western blotting, was not abnormal, however. Additionally, using in vivo 1H magnetic resonance spectroscopy we demonstrated an increased level of myoinositol in brains of Ts65Dn compared with control mice, consistent with our prior demonstration of increased myoinositol in brains of Down syndrome subjects. Thus, abnormal phosphoinositide signaling may contribute to mental retardation in Down syndrome, and can be examined in an appropriate mouse model. Kainate receptor-mediated excitatory postsynaptic currents occur in the spinal cord and are involved in nociception. Novel non-NMDA antagonists that we developed as anti-pain medication were shown to interfere with the effect of kainate in the rat spinal cord. - Kainate, Long-term potentiation, Long-term depression, Hippocampus, Down syndrome, Trisomy 65Dn mouse

节段三体小鼠（TS65DN）是人类唐氏综合征的动物模型（三体症21）。仅对于16染色体的片段，它与人类染色体21同源。成年TS65DN小鼠在空间任务上表现出异常学习。我们发现，来自该小鼠的孤立海马还表现出异常的长期增强（LTP）和长期抑郁（LTD），即学习和记忆模型。但是，通过蛋白质印迹估算的NMDA受体主亚基（NR1）和α-1C CA2+通道亚基蛋白的表达并非异常。此外，使用体内1H磁共振光谱学与对照小鼠相比，TS65DN的大脑中的肌异素醇水平升高，这与我们先前证明唐氏综合症受试者大脑中肌无素醇的证明相一致。因此，异常的磷酸肌醇信号传导可能会导致唐氏综合症的智力低下，并且可以在适当的小鼠模型中进行检查。海藻酸盐受体介导的兴奋性突触后电流发生在脊髓中，并参与伤害感受。我们发展为抗PAIN药物的新型非NMDA拮抗剂显示出干扰大鼠脊髓中海藻酸盐的作用。 - 海藻酸盐，长期增强，长期抑郁症，海马，唐氏综合症，三体疾病65dn小鼠