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

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不止一个信号级联，从而介导不止一个细胞内信息。同样的信号分子如何告诉两种或两种以上生物学上不同的细胞内信息的内容是令人困惑的。解决这一难题的一个有效方法是研究依赖于钙离子的神经元突触可塑性的双向调节机制。长期增强（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被广泛接受的模型。LTP和LTP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区别诱导的，依赖于相同的细胞内Ca2+离子。本项目的研究结果表明，细胞内Ca2+可以携带更多的信息来启动LTP或LTP的鉴别诱导。本项目发现了一种新的钙释放形式，它是由内质网上的IP_3受体通过钙和IP_3两种配体协同激活引起的。这种新的钙释放被进一步证明与活动依赖的负反馈动作电位放电调节相关。这些发现似乎对新皮层生理学有许多启示。首先，可能存在一种连接IP3受体和电压依赖性钙通道的新型锚定分子。其次，目前的新钙释放可能提供了一个“慢”、依赖神经调节剂的皮质投射系统和“快”系统之间相互作用的位点，这最直接影响细胞内钙浓度。第三，这种新的钙释放可能在不阻止基本神经元活动的情况下防止兴奋性毒性神经元死亡，因此可能在治疗上有用。最后一种可能性在本研究中得到了实验支持。少

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