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Memory and learning disorder analysis using mutation mouse for mental retadation related gene ATRX and elucidation of the genetic control abnormality.

使用智力迟缓相关基因 ATRX 突变小鼠进行记忆和学习障碍分析，并阐明遗传控制异常。

基本信息

批准号：
15500210
负责人：
KITAJIMA Isao
金额：
$ 2.37万
依托单位：
TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

The causative gene of the ATRX syndrome, which maps on chromosome X and shows such phenotypes as mental retardation and α thalassemia, is clarified. It has been reported that intelligence is lowered when exon 2 is mutated. Then, in cooperation with Dr.En Li and Dr.H.Beppu (Harvard University, USA), we performed back-crossing in the C57BL6 mouse system from the 129 mouse system to six generations (N6) in order to produce the ATRX mutant mouse for behavioral analysis. Using the C75BL6, N6 generation mouse, the following results were obtained over the two-year research period from 2003 to 2004. (1) The mutant mice have kock in highly Lac Z gene at the mutation site. The Lac Z gene was well observed in the hippocampus, cerebral cortex and cerebellum by X-gal staining. (2) Immunostaining was carried out with an antibody that recognized the C-terminus of ATRX. As a result, in comparison with the wild type, the low expression of the ATRX protein in the cerebral cortex, cerebellum, and hippoca … More mpus was recognized in the ATRX mutant mouse. (3) Using the antibody that recognized the C-terminus of ATRX, the mutant mouse showed decreased protein expression of approximately 50% in brain tissues by Western blot, in comparison with the wild type. (4) It is well known that the hippocampus controls memory and learning. Therefore, in order to analyze its function, we examined spatial memory learning with the Morris water maze test, and found that memory and learning capability of the mutant mouse were inferior to those of the wild type. This finding was confirmed in the diet remuneration test under the environment which removed aquaphobia. We also performed the open field test and the home cage activity test in order to examine other behavioral disorders of the mutant mouse. From these tests, we noted hyperactivity in the mutant mouse. Although it was affected by bright light in the wild type mouse, the sojourn time in the light-dark environment was reversed in the mutant mouse. The behavioral analysis revealed that the ATRX mutant mouse presented with low learning capability, photophobia sensitivity and hyperactivity. Less

阐明了ATRX综合征的致病基因定位于X染色体上，表现为智力低下和α地中海贫血等表型。据报道，当外显子2突变时，智力会降低。然后，我们与En Li博士和H.别府博士（哈佛大学，美国）合作，在C57 BL 6小鼠系统中进行从129小鼠系统到六代（N6）的回交，以产生用于行为分析的ATRX突变小鼠。使用C75 BL 6，N6代小鼠，在2003年至2004年的两年研究期间获得了以下结果。(1)突变小鼠Lac Z基因在突变位点具有高度的科克性。X-gal染色显示Lac Z基因在海马、大脑皮质和小脑中表达较好。(2)用识别ATRX的C-末端的抗体进行免疫染色。结果，与野生型相比，ATRX蛋白在大脑皮层、小脑和小脑中的低表达被证明是正常的。关于我们在ATRX突变小鼠中识别mpus。(3)使用识别ATRX的C-末端的抗体，与野生型相比，突变小鼠通过Western印迹显示脑组织中约50%的蛋白质表达降低。(4)众所周知，海马体控制记忆和学习。因此，为了分析其功能，我们用Morris水迷宫测试检测了空间记忆学习，发现突变小鼠的记忆和学习能力低于野生型小鼠。这一发现在消除了恐水症的环境下的饮食报酬试验中得到了证实。我们还进行了旷场试验和笼内活动试验，以检查突变小鼠的其他行为障碍。从这些测试中，我们注意到突变小鼠的多动症。虽然野生型小鼠受到强光的影响，但在突变型小鼠中，光暗环境中的逗留时间被逆转。行为学分析显示，ATRX突变小鼠表现为学习能力低下、恐惧敏感和多动。少