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) 是人类唐氏综合症（21 三体）的动物模型。仅与人类 21 号染色体同源的 16 号染色体片段是三体性的。成年 Ts65Dn 小鼠在空间任务上表现出异常学习能力。我们发现这只小鼠的离体海马体也表现出异常的长期增强（LTP）和长期抑制（LTD），这是学习和记忆的模型。然而，通过蛋白质印迹法估计，NMDA 受体主亚基 (NR1) 和 α-1C Ca2+ 通道亚基蛋白的表达并无异常。此外，使用体内 1H 磁共振波谱，我们证明与对照小鼠相比，Ts65Dn 大脑中肌醇的水平有所增加，这与我们之前证明的唐氏综合症受试者大脑中肌醇水平增加的情况一致。因此，异常的磷酸肌醇信号传导可能导致唐氏综合症的智力迟钝，并且可以在适当的小鼠模型中进行检查。红藻氨酸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。我们开发的新型非 NMDA 拮抗剂作为抗痛药，被证明可以干扰红藻氨酸对大鼠脊髓的作用。 - 红藻氨酸、长时程增强、长期抑制、海马、唐氏综合症、三体 65Dn 小鼠