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.

我们已经研究了1型肌醇14,5-三磷酸受体（IP3R1）在中枢神经系统形态发生和行为发展中的作用。在缺乏基因靶向产生的IP3R1的小鼠中，微观检查显示，大脑的每个结构的组织学部分没有异常，而这些结构被血氧基蛋白 - eosin或抗微动物介导的蛋白质染色。 / - ）没有IP3R1蛋白质，但是IP3R2和IP3R3的正常量。在纯合小鼠的整个大脑中，IP3结合显着降低。在9日（PND）的9日，纯合子开始表现出共济失调。在PND 15时，出现了截短的tros脚，PND 20-23占据了重复的滋补或滋补性癫痫发作。脑电图显示阵发性polyspike Activites。通过腹膜内注射戊巴比妥或地西epa抑制这种广泛的癫痫发作。综上所述，IP3R1似乎不仅在小脑功能，而且在神经网络的兴奋性方面起着重要作用。

项目成果

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)。

Tanaka K,Fukuuchi Y,Gomi S et al: "Reduction in second-messenger ligand binding sites after brain ischemia." Brain Res Bull. 32. 49-56 (1993)

Tanaka K、Fukuuchi Y、Gomi S 等人：“脑缺血后第二信使配体结合位点减少。”

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。”

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

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。

MATSUMOTO M,NAGATA E,TANAKA K et al.: "Ataxia and epileptic seizures in mice lacking type 1 inositol 1, 4, 5-trisphosphate receptor." Nature. 379. 168-171 (1996)

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。”