Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling
Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling
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DOI：
10.1523/jneurosci.2213-04.2004
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发表时间：
2004-11-24
影响因子：
5.3
通讯作者：
Balschun, D
中科院分区：
文献类型：
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作者：
Huang, KP;Huang, FL;Balschun, D
在神经元中，神经粒蛋白（Ng）与钙调蛋白（CaM）结合，其结合亲和力因Ca2+增加、PKC磷酸化或氧化剂氧化而降低。成年小鼠海马中Ng浓度变化较大(Ng(+/+)，近似于160 ~ 370 pmol/mg； Ng(+/-)，近似于70 ~ 230 pmol/mg)；在所有神经元cam结合蛋白中，Ng（+/+）小鼠的表达水平最高。在Ng（+/-）小鼠中，但在Ng（+/+）小鼠中不太明显，海马Ng水平与Morris水迷宫的表现之间存在显著关系。Ng（-/-）小鼠在这项任务中表现不佳；海马CA1区高频诱发的长期增强（LTP）功能也出现缺陷，而低频诱发的长期抑郁则增强。因此，与Ng（+/+）小鼠相比，Ng（-/-）的频响曲线向右偏移。在长时间10hz（900脉冲）刺激下，配对脉冲易化和突触疲劳在Ng（-/-）切片中没有变化，表明它们的突触前功能正常。在弱和强强电刺激（分别为100 Hz， 400和1000 msec）后CA1锥体神经元Ca2+瞬态的测量显示，与Ng（-/-）小鼠相比，Ng（+/+）小鼠细胞内Ca2+([Ca2+](i))反应显著增加，但衰减时间常数没有差异。在Ng（-/-）小鼠中Ca2+动力学的减弱可能是其经历LTP倾向降低的原因。因此，Ng可能通过“质量作用”机制促进高[Ca2+](i)；即，Ng浓度越高，形成的Ng- cam络合物越多，在任何给定的Ca2+内流时，这有效地提高了[Ca2+](i)。这一机制为增强突触可塑性和学习记忆提供了强有力的信号放大机制。
In neurons, neurogranin (Ng) binds calmodulin (CaM), and its binding affinity is reduced by increasing Ca2+, phosphorylation by PKC, or oxidation by oxidants. Ng concentration in the hippocampus of adult mice varied broadly (Ng(+/+), similar to160-370 and Ng(+/-), similar to70-230 pmol/mg); the level in Ng(+/+) mice is one of the highest among all neuronal CaM-binding proteins. Among Ng(+/-) mice, but less apparent in Ng(+/+), a significant relationship existed between their hippocampal levels of Ng and performances in the Morris water maze. Ng(-/-) mice performed poorly in this task; they also displayed deficits in high-frequency-induced long-term potentiation (LTP) in area CA1 of hippocampal slices, whereas low-frequency-induced long-term depression was enhanced. Thus, compared with Ng(+/+) mice, the frequency-response curve of Ng(-/-) shifted to the right. Paired-pulse facilitation and synaptic fatigue during prolonged stimulation at 10 Hz (900 pulses) were unchanged in Ng(-/-) slices, indicating their normal presynaptic function. Measurements of Ca2+ transients in CA1 pyramidal neurons after weak and strong tetanic stimulations (100 Hz, 400 and 1000 msec, respectively) revealed a significantly greater intracellular Ca2+([Ca2+](i)) response in Ng(+/+) compared with Ng(-/-) mice, but the decay time constants did not differ. The diminished Ca2+ dynamics in Ng(-/-) mice are a likely cause of their decreased propensity to undergo LTP. Thus, Ng may promote a high [Ca2+](i) by a "mass-action" mechanism; namely, the higher the Ng concentration, the more Ng-CaM complexes will be formed, which effectively raises [Ca2+](i) at any given Ca2+ influx. This mechanism provides potent signal amplification in enhancing synaptic plasticity as well as learning and memory.