Prediction and validation of a mechanism to control the threshold for inhibitory synaptic plasticity.
Prediction and validation of a mechanism to control the threshold for inhibitory synaptic plasticity.
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DOI：
10.1038/msb.2009.39
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发表时间：
2009
影响因子：
9.9
通讯作者：
Kawaguchi, Shin-ya
中科院分区：
文献类型：
--
作者：
Kitagawa, Yuichi;Hirano, Tomoo;Kawaguchi, Shin-ya
突触可塑性是学习和记忆的基础，突触的可塑性是突触传递效能的持续变化。通过增加细胞内钙离子浓度([Ca~(2+)]i)激活正反馈信号通路与突触可塑性有关。然而，确定诱导突触可塑性的[Ca~(2+)]i阈值的机制尚不清楚。在这里，我们建立了小脑抑制性突触可塑性的动力学模拟模型，并系统地分析了由蛋白激酶、磷酸酶等组成的复杂分子网络的行为。模拟表明，在突触可塑性诱导中必不可少的钙/钙调蛋白依赖性蛋白激酶II(CaMKII)在不同的刺激组合中被持续激活或抑制。CaMKII的持续激活依赖于两个正反馈反应的协同作用，即CaMKII的自动磷酸化和CaMKII介导的对CaM依赖的磷酸二酯酶PDE1的抑制。模拟预测，PDE1介导的前馈抑制CaMKII主要控制钙阈值，这一点在原代小脑培养的电生理实验中得到了证实。因此，模拟和实验相结合的应用表明，小脑抑制性突触可塑性的钙阈值主要由PDE1决定。
Synaptic plasticity, neuronal activity-dependent sustained alteration of the efficacy of synaptic transmission, underlies learning and memory. Activation of positive-feedback signaling pathways by an increase in intracellular Ca2+ concentration ([Ca2+]i) has been implicated in synaptic plasticity. However, the mechanism that determines the [Ca2+]i threshold for inducing synaptic plasticity is elusive. Here, we developed a kinetic simulation model of inhibitory synaptic plasticity in the cerebellum, and systematically analyzed the behavior of intricate molecular networks composed of protein kinases, phosphatases, etc. The simulation showed that Ca2+/calmodulin-dependent protein kinase II (CaMKII), which is essential for the induction of synaptic plasticity, was persistently activated or suppressed in response to different combinations of stimuli. The sustained CaMKII activation depended on synergistic actions of two positive-feedback reactions, CaMKII autophosphorylation and CaMKII-mediated inhibition of a CaM-dependent phosphodiesterase, PDE1. The simulation predicted that PDE1-mediated feedforward inhibition of CaMKII predominantly controls the Ca2+ threshold, which was confirmed by electrophysiological experiments in primary cerebellar cultures. Thus, combined application of simulation and experiments revealed that the Ca2+ threshold for the cerebellar inhibitory synaptic plasticity is primarily determined by PDE1.
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影响因子：
3.5
作者：
Kawaguchi, SY;Hirano, T
通讯作者：
Hirano, T
影响因子：
5.3
作者：
Houston, Catriona M.;Hosie, Alastair M.;Smart, Trevor G.
通讯作者：
Smart, Trevor G.
影响因子：
16.2
作者：
Kawaguchi, S;Hirano, T
通讯作者：
Hirano, T
DOI：
10.1126/science.1160617
发表时间：
2008-10-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Brandman O;Meyer T
通讯作者：
Meyer T
影响因子：
5.3
作者：
Kawaguchi, S;Hirano, T
通讯作者：
Hirano, T