PATHOGENESIS OF DEMENTIA IN AMYOTROPHIC LATERAL SCLEROSIS (ALTERATION OF INOSITOL 1,4,5-TRISPHOSPHATE (IP3) RECETOR AND RYANODINE RECEPTOR IN THE HIPPOCAMPUS)

肌萎缩侧索硬化症痴呆的发病机制（海马肌醇 1,4,5-三磷酸 (IP3) 受体和兰尼碱受体的改变）

• 批准号: 05670572
• 负责人: TANAKA Kotaro
• 金额: $ 1.22万
• 依托单位: KEIO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670572/
• 关键词: AMYOTROPHIC LATERAL SCLEROSIS; DEMENTIA; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; HIPPOCAMPUS; RYANODINE RECEPTOR; イノシトール1,4,5三リン酸受容体

We have investigated the role of type 1 inositol 14,5-trisphosphate receptor (IP3R1) in the morphogenesis of the central nervous system and the behavioral development. In mice lacking IP3R1 generated by gene targeting, microscopic examination revealed no abnormality in the histological sections of each structure fo the brain, which were stained by hematoxyline-eosin or anti-microtubule-associated protein 2. Western blot analysis showed that homozygote (IR3R1 -/-) has no IP3R1 protein, but normal amounts of IP3R2 and IP3R3. IP3 binding was significantly reduced all over the brain in the homozygote mice. At postnatal day (PND) of 9, homozygote began to show ataxia. At PND 15, truncal trosion appeared, and repetitive tonic or tonic-clonic seizures prevailed by PND 20-23. Electroencephalogram showed a paroxysmal polyspike activites. Such generalized seizures were suppressed by intraperitoneal injection of pentobarbital or diazepam. Taken together, IP3R1 seems to play an important role in the regulation of not only cerebellar function but also of the excitability of the neural networks.

本研究探讨了14，5-三磷酸肌醇1型受体（IP 3R 1）在中枢神经系统形态发生和行为发育中的作用。在缺乏基因靶向产生的IP 3R 1的小鼠中，显微镜检查显示脑的每个结构的组织切片中没有异常，这些组织切片被苏木精-伊红或抗微管相关蛋白2染色。Western blot分析表明，纯合子（IR 3R 1-/-）没有IP 3R 1蛋白，但正常量的IP 3R 2和IP 3R 3。在纯合子小鼠中，IP 3结合在整个大脑中显著降低。在出生后第9天，纯合子开始出现共济失调。在PND 15时，出现躯干扭转，并且在PND 20-23时反复强直性或强直阵挛性癫痫发作占优势。脑电图呈阵发性多棘波活动。腹腔注射戊巴比妥或地西泮可抑制全身性癫痫发作。总之，IP 3R 1似乎不仅在小脑功能的调节中，而且在神经网络的兴奋性的调节中发挥重要作用。

项目成果

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野崎博之、田中耕太郎他: "砂ネズミ脳虚血におけるRyanodine受容体の変化に関する研究" 神経化学. 32. 82-83 (1993)

Hiroyuki Nozaki、Kotaro Tanaka 等：“沙鼠脑缺血中 Ryanodine 受体变化的研究”《神经化学》32. 82-83 (1993)。

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NAGATA E、TANAKA K 等人：“沙鼠大脑半球缺血六小时后肌醇 1,4,5-三磷酸受体的改变”神经科学。

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MATSUMOTO M、NAGATA E、TANAKA K 等人：“缺乏 1 型肌醇 1,4,5-三磷酸受体的小鼠出现共济失调和癫痫发作。”

NAGATA E, TANAKA K et al.: "Alteration of inositol 1,4,5-trisphosphate receptor six-hour hemispheric ischemia in the gerbil braiv." Neuroscience. 61. 983-990 (1994)

NAGATA E、TANAKA K 等人：“沙鼠 Braiv 中肌醇 1,4,5-三磷酸受体六小时半球缺血的改变。”