Elucidation of molecular mechanisms for post-birth development of learning abilities and its application to learning

阐明出生后学习能力发展的分子机制及其在学习中的应用

基本信息

批准号：
15200024
负责人：
MANABE Toshiya
金额：
$ 25.79万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

The mechanism for the process of the development of learning abilities in the mammal is almost totally unknown. In this research project, we have tried to elucidate its molecular and cellular mechanism and to obtain basic results that could be used in future to improve the learning method. For this purpose, we have used hippocampal and amygdaloid slice preparations of normal and gene-targeted mutant mice to analyze synaptic transmission and plasticity electrophysiologically. In knockin mice lacking mouse apoE, but instead expressing human apoE4, LTP in the CAl region is enhanced at younger age, while LTP is unchanged in adult mice. Since basal synaptic transmission and distribution of glutamate receptors, as well as presynaptic functions, are intact in apoE4 mutant mice, age-dependent postsynaptic functional modification of LTP through lipid homeostasis is suggested. We have also examined mutant mice deficient in Ptprz, using electrophysiological, pharmacological and behavioral approaches. Mutant mice exhibit enhanced LTP in the CAl region of hippocampal slices and impaired spatial learning abilities in an age-dependent manner: young adult (less than 10 weeks old) mutant mice show normal LTP and learning abilities in Morris water maze task, whereas adult (more than 13 weeks old) mutant mice exhibit enhanced LTP and impairment in the task. The enhanced LTP is specifically canceled out by the ROCK inhibitor Y-27632. These findings suggest that the lack of Ptprz leads to aberrant activation of ROCK, and resultantly to enhanced LTP in the slice and learning impairments in the whole animal. We have also analyzed many other kinds of mutant mice lacking functional molecules, and published many research papers in scientific journals.

哺乳动物学习能力发展过程的机制几乎完全未知。在这个研究项目中，我们试图阐明其分子和细胞机制，并获得可用于将来改进学习方法的基本结果。为此，我们使用正常小鼠和基因靶向突变小鼠的海马和杏仁切片制剂来分析突触传递和可塑性电生理学。在缺乏小鼠apoE但表达人apoE4的敲入小鼠中，CA1区中的LTP在年轻时增强，而LTP在成年小鼠中没有变化。由于 apoE4 突变小鼠的基础突触传递和谷氨酸受体分布以及突触前功能是完整的，因此建议通过脂质稳态对 LTP 进行年龄依赖性突触后功能修饰。我们还使用电生理学、药理学和行为学方法检查了 Ptprz 缺陷的突变小鼠。突变小鼠在海马切片的 CA1 区域表现出增强的 LTP，并且以年龄依赖性方式受损的空间学习能力：年轻成年（小于 10 周龄）突变小鼠在 Morris 水迷宫任务中表现出正常的 LTP 和学习能力，而成年（超过 13 周龄）突变小鼠表现出 LTP 增强和任务障碍。 ROCK 抑制剂 Y-27632 专门抵消了增强的 LTP。这些发现表明，Ptprz 的缺乏会导致 ROCK 的异常激活，从而导致切片中的 LTP 增强和整个动物的学习障碍。我们还分析了许多其他种类的缺乏功能分子的突变小鼠，并在科学期刊上发表了许多研究论文。