Functional analysis of the glutamate receptor δ2 subunit in the motor learning

谷氨酸受体δ2亚基在运动学习中的功能分析

• 批准号: 10680716
• 负责人: MORI Hisashi
• 金额: $ 2.18万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10680716/
• 关键词: Glutamate receptor; GluRδ2 subunit; Motor learning; Eye blink conditioning; Cerebellar Purkinje cells; Cerebellar granule cells; Cre recombinase; 遺伝子ノックアウト; テトラサイクリンオペロン; 小脳

Glutamate receptor (GluR) channels mediate most of fast excitatory synaptic transmission in the vertebrate central nervous system. The GluRδ2 subunit expressed specifically in cerebellar Purkinje cells, and it's ablation resulted in impairements of long term depression (LTD), motor coordination, and refinement of synapses. GluRδ2 deficient mice received classical eyeblink conditioning. In the delay paradigm in which the conditioned stimuluus (CS) overlapped temporally with unconditioned stimulus (US). GluRδ2 mutant mice exhibited a severe impairment in learning. However, in the trace paradigm in which a stimulus-free trace interval intervened between the CS and US. GluRδ2 mutant mice learned as successfully as wild-type mice. Therefore, cerebellar LTD is essential in the delay paradigm, but not in the trace paradigm, suggesting an alteration of cerebellar neural substrates underlying eyeblink conditioning depending on the temporal overlap of the CS and US. Furthermore, to develop a cell type-specific and temporal regulation system of gene targeting in the cerebellum, we employed the NMDA receptor GluRε3 subunit gene and Cre recombinase-progesterone receptor fusion (CrePR) gene in combination. We established a ECP25 transgenic mouse line that strongly expressed the CrePR mRNA selectively in the granule cells of the cerebellum. We showed that antiprogestins could induce the recombinase activity of CrePR fusion protein of ECP25 mouse in the cerebellar granule cells. Thus, the established mouse line will provide a valuable tool to investigate the mechanism of cerebellar function by manipulating molecules in the temporally regulated and granule cell-specific manner.

谷氨酸接收器（GLUR）通道介导脊椎动物中枢神经系统中的大部分快速兴奋性突触传播。 GlurΔ2亚基在小脑Purkinje细胞中特别表达，这是烧蚀导致长期抑郁症（LTD），运动协调和突触的细化的损害。 GLURΔ2缺乏小鼠接受了经典的眉毛调节。在条件刺激（CS）暂时与无条件刺激（US）暂时重叠的延迟范式中。 GlurΔ2突变小鼠在学习中暴露了严重的障碍。但是，在痕量范式中，CS和我们之间的无刺激痕量间隔。 GlurΔ2突变小鼠与野生型小鼠一样成功地学习。因此，小脑有限公司在延迟范式中至关重要，但在痕量范式中不是必不可少的，这表明根据CS和US的暂时重叠，在眉毛条件下的小脑神经底物改变了小脑神经底物。此外，为了开发小脑中靶向基因的细胞类型和临时调节系统，我们采用了NMDA受体Glurε3亚基基因和CRE重组酶 - 蛋白酶 - 蛋白酶融合（CREPR）基因。我们建立了ECP25转基因小鼠系，该系在小脑的颗粒细胞中有选择地表达CREPR mRNA。我们表明，抗膜蛋白可以诱导小脑颗粒细胞中ECP25小鼠CREPR融合蛋白的重组酶活性。这是，已建立的小鼠系将提供一个有价值的工具，通过以暂时调节和颗粒细胞特异性方式操纵分子来研究小脑功能的机理。

项目成果

Kiyama, Y., et al.: "Increased thresholds for long-term potentiation and contexual learning in mice lacking the NMDA-type glutamate receptor ε1 subunit"Journal of Neuroscience. 18. 6704-6712 (1998)

Kiyama, Y.等人：“缺乏 NMDA 型谷氨酸受体 ε1 亚基的小鼠的长期增强和情境学习阈值增加”《神经科学杂志》18. 6704-6712 (1998)。

Mori Hisashi et al.: "Role of the carboxy-terminal region of the GluR ε_2 Subumit in symaptic localization of the NMDA receptor channel" Neuron. 21. 571-580 (1998)

Mori Hisashi 等人：“GluR ε_2 亚基的羧基末端区域在 NMDA 受体通道的交感定位中的作用”Neuron。 21. 571-580 (1998)

Mika Tsujita et al.,: "Cerebellar Granule Cell-Specific and Inducible Expression of Cre Recombinase in the Mouse"Journal of Neuroscience. 19(23). 10318-10323 (1999)

Mika Tsujita 等人，“Cre 重组酶在小鼠中的小脑颗粒细胞特异性和诱导表达”神经科学杂志。

Morikawa E. et al.: "Attenuation of focal ischemic brain injury in mice deficient in the ε1 (NR2A) subunit of NMDA receptor."J. Neurosci.. 18. 9727-9732 (1998)

Morikawa E. 等人：“NMDA 受体 ε1 (NR2A) 亚基缺陷的小鼠局灶性缺血性脑损伤的减轻。J. Neurosci.. 18. 9727-9732 (1998)

Kiyama Yuji et al.: "Increased threshelds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor ε_1 subunit" Journal of Neuroscience. 18. 6704-6712 (1998)

Kiyama Yuji 等人：“缺乏 NMDA 型谷氨酸受体 ε_1 亚基的小鼠长期增强和情境学习的阈值增加”《神经科学杂志》18. 6704-6712 (1998)。