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Basic research for understanding the molecular mechanism of mental retardation and the development of the treatment and diagnostic methods for the disease.

了解精神发育迟滞的分子机制以及开发该疾病的治疗和诊断方法的基础研究。

基本信息

批准号：
18591156
负责人：
MITSUI Shinichi
金额：
$ 2.57万
依托单位：
Kochi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591156/
关键词：
Mental retardation Developmental disorder Serine protease Neurotrvpsin Social behavior Learning and memory

项目摘要

Our aim is the development of novel therapy and diagnostic method for developmental disorders based on the molecular mechanism of the disease. In this study, we analyzed 1) the behavioral phonotype of mice lacking a mental retardation gene, motopsin (prss12), and 2) spatio-temporal localization of a motopsin-interacting protein, SEZ6.Motopsin-deficient mice showed moderately impaired spatial memory. A social memory test failed to reveal abnormality, however, the mutant mice showed prolonged sniffing to a stranger mouse. In a social novelty test, motopsin-deficient mice showed prolonged interest even in a familiar mouse. Consistent with such behavioral deficits, the spine density on apical dendrites of pyramidal neurons was significantly decreased at hippocampus CA1 region, which is known to be crucial for spatial memory and social behavior.We have previously identified SEZ6 as a motopsin-binding protein. SEZ6 immunoreactivity (IR) was detected at the hippocampal CA1 region, cerebral cortex, lateral amygdala, and caudate putamen using anti-SEZ6 antibody, which was prepared against recombinant SEZ6 protein. It was noted that SEZ6 IR was obvious in the cerebral cortex at postnatal day (P) 7 and the CA1 hippocampus at P10, suggesting interaction with motopsin in these regions. Similar localization was observed in the human brain and spinal cord.Our results suggest that motopsin secreted from neuronal cells anchors to SEZ6 proteins on neurons and that lack of motopsin function causes some symptom of mental retardation, eg, impaired memory formation and abnormal social behavior, through the defect of hippocampal function.

我们的目标是发展新的治疗和诊断方法的基础上，疾病的分子机制的发育障碍。在这项研究中，我们分析了1）缺乏精神发育迟滞基因motopsin（prss12）的小鼠的行为表型，和2）motopsin相互作用蛋白SEZ6的时空定位。Motopsin缺陷小鼠表现出中度受损的空间记忆。社交记忆测试未能发现异常，然而，突变小鼠对陌生小鼠表现出长时间的嗅探。在一项社会新奇性测试中，缺乏motopsin的小鼠甚至对熟悉的小鼠也表现出了长期的兴趣。与这种行为缺陷相一致的是，海马CA1区锥体神经元顶树突上的棘密度显著降低，这是已知的空间记忆和社会行为的关键。SEZ6免疫反应性（IR）检测在海马CA1区，大脑皮层，杏仁外侧核，尾壳核使用抗SEZ6抗体，这是针对重组SEZ6蛋白制备。结果表明，SEZ 6免疫反应在生后7天（P）的大脑皮层和生后10天的海马CA1区明显，表明在这些区域与motopsin相互作用。我们的研究结果表明，从神经元细胞分泌的motopsin锚定在神经元上的SEZ6蛋白，motopsin功能的缺乏会通过海马功能的缺陷导致智力低下的一些症状，如记忆形成障碍和异常的社会行为。