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

哺乳动物学习能力发展过程的机制几乎是完全未知的。在本研究项目中，我们试图阐明其分子和细胞机制，并获得可用于未来改进学习方法的基本结果。为此，我们利用正常小鼠和基因靶向突变小鼠的海马和杏仁核切片制备，从电生理上分析突触传递和可塑性。在缺乏小鼠apoE但表达人类apoE4的敲入小鼠中，CAl区域的LTP在年轻时增强，而成年小鼠的LTP不变。由于谷氨酸受体的基础突触传递和分布以及突触前功能在apoE4突变小鼠中是完整的，因此可以通过脂质稳态对LTP进行年龄依赖性的突触后功能修饰。我们还使用电生理学、药理学和行为学方法研究了Ptprz缺乏的突变小鼠。突变小鼠海马CAl区LTP增强，空间学习能力受损，并呈年龄依赖性：年轻成年（小于10周龄）突变小鼠在Morris水迷宫任务中LTP和学习能力正常，而成年（大于13周龄）突变小鼠在Morris水迷宫任务中LTP增强，空间学习能力受损。增强的LTP被ROCK抑制剂Y-27632特别抵消。这些发现表明，Ptprz的缺乏导致ROCK异常激活，从而导致切片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。

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.