Molecular mechanisms of synaptic plasticity : specific involvement of various aspects of calcium dependent processes

突触可塑性的分子机制：钙依赖性过程各个方面的具体参与

基本信息

批准号：
09480229
负责人：
KATO Nobuo
金额：
$ 7.23万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 2000
项目状态：
已结题

项目摘要

In neurons and non-excitable cells alike, single intracellular signaling molecules seem to be involved in more than one signaling cascade, so as to mediate more than one intracellular messages. How the same signal molecule tells two or more biologically different contents of intracellular messages is puzzling. One fruitful approach to address this puzzle would be to study the mechanism of bi-directional regulation of synaptic plasticity in neurons, which is dependent on the calcium ion. Long-term potentiation (LTP) and depression (LTD), which represent up- and down-regulations of synaptic efficiency respectively, are widely accepted models for studying molecular mechanisms of memory. Increases of intracellular Ca2+ concentration are required for induction of both LTP and LTD.These two types of synaptic regulations are shown to be discriminately induced, depending on the same intracellular Ca2+ ions. The findings obtained in the present project suggest that intracellular Ca2+ can carry … More sufficient information to initiate discriminative induction of LTP or LTD.The present project discovered a novel form of calcium release, which is caused by a synergistic activation of the IP_3 receptors on the endoplasmic reticulum by its two ligands calcium and IP_3. This novel calcium release was further demonstrated to correlate with an activity-dependent, negative feedback regulation of action potential firing. These findings seem to have a number of implications on neocortical physiology. First, a novel anchor molecule might exist which links IP3 receptors and voltage-dependent calcium channels. Second, the present novel calcium release may provide a site of interaction between the "slow", neuromodulator-dependent cortical projection system and the "fast" system, which most directly affects intracellular calcium concentration. Third, this novel calcium release may prevent excitotoxic neuronal death without preventing basic neuronal activity, and could therefore be therapeutically useful. The last possibility was experimentally supported in the present study. Less

在神经元和非兴奋性细胞中，单个细胞内信号分子似乎参与多个信号级联，从而介导多个细胞内信息，这就是同一信号分子如何告知细胞内信息的两种或多种生物学不同内容。解决这个难题的一种有效方法是研究神经元突触可塑性的双向调节机制，该机制依赖于长时程增强（LTP）和抑制（LTD），分别代表突触效率的上调和下调，是研究记忆分子机制的广泛接受的模型。LTP 和 LTD 的诱导都需要细胞内 Ca2+ 浓度的增加。这两种类型的突触调节被证明是有区别的。诱导，取决于相同的细胞内 Ca2+ 离子本项目中获得的发现表明，细胞内 Ca2+ 可以携带更多信息来区分充分诱导 LTP 或 LTD。本项目发现了一种新型钙。释放，这是由其两个配体钙和 IP_3 协同激活内质网上的 IP_3 受体引起的，这种新型钙释放被进一步证明与动作电位放电的活动依赖性负反馈调节相关。首先，可能存在一种连接 IP3 受体和电压依赖性钙通道的锚定分子；其次，目前的新型钙释放可能提供了相互作用的位点。第三，这种新型钙释放可以防止兴奋毒性神经元死亡，而不妨碍基本神经元活动，因此可能具有治疗作用。在本研究中，这种可能性得到了实验的支持。