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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15200024/
• 关键词: glutamate; NMDA receptor; hippocampus; amygdala; learning and memory; synaptic transmission; plasticity; mouse; 恐怖学習; 海馬; 扁桃体; アセチルコリン; チロシリン酸化; アルツハイマー病; 記憶; 発達

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。

项目成果

Age-Dependent Enhancement of Hippocampal Long-Term Potentiation and Impairment of Spatial Learning through the Rho-Associated Kinase Pathway in Protein Tyrosine Phosphatase Receptor Type Z-Deficient Mice

• DOI: 10.1523/jneurosci.2565.04.2005
• 发表时间: 2005-02
• 期刊: The Journal of Neuroscience
• 作者: K. Niisato;A. Fujikawa;S. Komai;T. Shintani;E. Watanabe;G. Sakaguchi;G. Katsuura;T. Manabe;M. Noda

Roles of M_2 and M_4 muscarinic receptors in regulating acetylcholine release from myenteric neurons of mouse ileum.

M_2 和 M_4 毒蕈碱受体在调节小鼠回肠肌间神经元乙酰胆碱释放中的作用。

• 发表时间: 2005
• 期刊: Journal of Neurophysiology 93
• 作者: Takeuchi;T.;Fujinami;K.;Goto;H.;Fujita;A.;Taketo;M.M.;Manabe;T.;Matsui;M.;Hata;F.
• 通讯作者: F.

Cystometric findings in mice lacking muscarinic M2 or M3 receptors

• DOI: 10.1097/01.ju.0000138054.77785.4a
• 发表时间: 2004-12-01
• 期刊: JOURNAL OF UROLOGY
• 影响因子: 6.6
• 作者: Igawa, Y;Zhang, XY;Andersson, KE
• 通讯作者: Andersson, KE

Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor.

缺乏AP-3B网格蛋白适配器的小鼠中含GABA的突触囊泡的功能不良。

• DOI: 10.1083/jcb.200405032
• 发表时间: 2004-10-25
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Nakatsu, Fubito;Okada, Motohiro;Mori, Fumiaki;Kumazawa, Noriko;Iwasa, Hiroto;Zhu, Gang;Kasagi, Yasufumi;Kamiya, Haruyuki;Harada, Akihiro;Nishimura, Kazuhiro;Takeuchi, Arata;Miyazaki, Taisuke;Watanabe, Masahiko;Yuasa, Shigeki;Manabe, Toshiya;Wakabayashi, Koichi;Kaneko, Sunao;Saito, Takashi;Ohno, Hiroshi
• 通讯作者: Ohno, Hiroshi

神経回路の機能発現のメカニズム

神经回路功能表达机制

• 发表时间: 2004
• 作者: 細江誠一郎;西野隆典;伊藤克亘;武田一哉;真鍋 俊也
• 通讯作者: 真鍋 俊也