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

我们研究了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育中的作用。在基因靶向产生的缺乏IP3R1的小鼠中，显微镜检查显示，用苏木精-伊红或抗微管相关蛋白2染色的脑组织各结构的组织学切片未见异常。Western blot分析显示，纯合子（IR3R1 -/-）不含IP3R1蛋白，IP3R2和IP3R3蛋白含量正常。纯合子小鼠全脑IP3结合明显减少。9岁出生后，纯合子开始出现共济失调。PND 15时出现躯干扭转，20-23时出现重复性强直性或强直性阵挛性发作。脑电图显示阵发性多峰活动。腹腔注射戊巴比妥或地西泮可抑制这种全身性癫痫发作。综上所述，IP3R1似乎不仅在调节小脑功能，而且在调节神经网络的兴奋性方面发挥重要作用。

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.