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Study on long-term potentiation of brain hippocampus

大脑海马长时程增强研究

基本信息

批准号：
04044134
负责人：
MIYAMOTO Eishichi
金额：
$ 3.46万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04044134/
关键词：
Hippocampus Memory Learning Synaptic long-term potentiation Glutamate receptor NMDA receptor Ca^<2+> mobilization CaM kinase II シナプス活動長期増強受容体阻害薬

项目摘要

Long-term potentiation of synaptic transmission which was first discovered in 1973 is now considered to be a primary model of human learning and memory. However, its mechanism has not been elucidated, although the molecular events of the phenomenon are supposed to underlie. Several lines of evidence indicated that the stimulation of the N-methyl-D-aspartate (NMDA) glutamate receptor in the postsynaptic cell triggers the long-term potentiation in CAl area of hippocampus and in turn causes the increase in Ca^<2+> influx. The elevation of the intracellular Ca^<2+> concentration results in activation of Ca^<2+>-dependent protein kinases.Among Ca^<2+>-dependent enzymes, CaM kinase II is of particular interest for two major reasons, 1) it is a major component of postsynaptic densities and 2) it is a multimeric holoenzyme, composed of several catalytic subunits, which may be autophosphorylated following activation by calcium and calmodulin and thereby remain active for a prolonged period of time. Among the molecular mechanisms that have been proposed to contribute to long-term potentiation in hippocampus are the activation and autophosphorylation of CaM kinase II. High, but not low frequency stimulation applied to two groups of CAl afferents resulted in a long lasting increase in the Ca^<2+>-independent and total activities of the enzyme as well as an increase in the ratio of Ca^<2+>-independent to total activity. The effect was obtained using two different CaM kinase II substrates, it was observed in hippocampal slices and in hippocampal organotypic cultures, and it could be blocked by preincubation of slices with the NMDA receptor antagonist D-2-amino-5-phosphonopentanoate. Treatment of slices with calyculin A, a phosphatase inhibitor, modified the activity of the enzyme, but long term potentiation could still be induced and a further increase in Ca^<2+>-independent CaM kinase II activity still observed.

突触传递的长期增强于 1973 年首次被发现，现在被认为是人类学习和记忆的主要模型。然而，尽管该现象的分子事件被认为是其基础，但其机制尚未阐明。多项证据表明，突触后细胞中N-甲基-D-天冬氨酸(NMDA)谷氨酸受体的刺激触发了海马CA1区域的长期增强，进而引起Ca^2+流入的增加。细胞内 Ca^<2+> 浓度的升高导致 Ca^<2+> 依赖性蛋白激酶的激活。在 Ca^<2+> 依赖性酶中，CaM 激酶 II 特别令人感兴趣，原因有两个：1) 它是突触后密度的主要成分，2) 它是一种多聚体全酶，由多个催化亚基组成，可能是被钙和钙调蛋白激活后发生自磷酸化，从而长时间保持活性。已提出的有助于海马体长期增强的分子机制之一是 CaM 激酶 II 的激活和自身磷酸化。对两组CA1传入神经施加高频率刺激，但不是低频刺激，导致酶的不依赖于Ca 2+ 的活性和总活性的持久增加，以及不依赖于总活性的Ca 2+ 的比率的增加。该效应是使用两种不同的 CaM 激酶 II 底物获得的，在海马切片和海马器官型培养物中观察到该效应，并且可以通过将切片与 NMDA 受体拮抗剂 D-2-氨基-5-磷酸戊酸预孵育来阻断该效应。用花萼蛋白A(一种磷酸酶抑制剂)处理切片改变了酶的活性，但仍可诱导长期增强，并且仍观察到不依赖于Ca 2+ 的CaM激酶II活性的进一步增加。