STDP in a bistable synapse model based on CaMKII and associated signaling pathways.
STDP in a bistable synapse model based on CaMKII and associated signaling pathways.
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DOI：
10.1371/journal.pcbi.0030221
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发表时间：
2007-11
影响因子：
4.3
通讯作者：
Brunel N
中科院分区：
文献类型：
--
作者：
Graupner M;Brunel N
钙/钙调蛋白依赖的蛋白激酶II(CaMKII)在钙内流后长时程突触后修饰的诱导中起关键作用。实验表明，这些长期的突触变化是在离散状态之间全有或无切换的事件。涉及CaMKII及其调控蛋白信号级联的生化网络被假设为以双稳态开关的形式持久地维持诱发的突触状态。然而，在这种网络的现实模型中，实验性的LTP/LTD协议是否会导致两个状态之间的相应转换仍然不清楚。我们提出了一个详细的CaMKII自动磷酸化的生化模型和控制CaMKII去磷酸化的蛋白质信号级联。如前所述，在静止的细胞内钙离子浓度下，CaMKII磷酸化水平存在两种稳定状态，高钙瞬变可以将系统从CaMKII的弱磷酸化(向下)切换到高度磷酸化(向上)状态(类似于LTP事件)。我们在这里表明，在中等钙离子浓度下，CaMKII去磷酸化活性的增加可以导致从上调状态切换到下调状态(类似于LTD事件)。如果促进CaMKII去磷酸化的蛋白磷酸酶活性在比激酶活性更低的钙离子水平上被激活，就可以实现这一点。最后，结果表明，CaMKII系统可以定性地再现峰时依赖可塑性(STDP)和突触前刺激方案的可塑性结果。这表明，CaMKII蛋白网络可以解释通过LTP/LTD样跃迁的诱导和由于其双稳性而导致的突触变化的存储。学习和记忆被认为是由于突触的改变而发生的。突触传递的有效性已被证明是突触前和突触后神经元之间相关活动的函数。长时间的突触修饰可以在两个方向上发生(长时程增强(LTP)和长时程抑制(LTD))。最近的实验表明，这些突触变化是要么全有要么全不开关的变化。这意味着只存在两种稳定的突触传递效率状态，即低状态或“关闭”状态和高状态或“开启”状态。LTP相当于打开突触，而LTD对应于关闭突触。我们提出了一个现实的蛋白质-蛋白质相互作用的生化模型，该模型呈现两个稳定状态。然后，我们研究了模型在两个稳定状态之间发生跃迁的条件。我们证明了已知的激发LTP和LTD的实验刺激协议导致了模型中相应的转变。这项工作支持这样的观点，即所研究的细胞内蛋白网络在突触变化的诱导和存储中都具有作用，从而在学习和记忆存储中发挥作用。
The calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in the induction of long-term postsynaptic modifications following calcium entry. Experiments suggest that these long-term synaptic changes are all-or-none switch-like events between discrete states. The biochemical network involving CaMKII and its regulating protein signaling cascade has been hypothesized to durably maintain the evoked synaptic state in the form of a bistable switch. However, it is still unclear whether experimental LTP/LTD protocols lead to corresponding transitions between the two states in realistic models of such a network. We present a detailed biochemical model of the CaMKII autophosphorylation and the protein signaling cascade governing the CaMKII dephosphorylation. As previously shown, two stable states of the CaMKII phosphorylation level exist at resting intracellular calcium concentration, and high calcium transients can switch the system from the weakly phosphorylated (DOWN) to the highly phosphorylated (UP) state of the CaMKII (similar to a LTP event). We show here that increased CaMKII dephosphorylation activity at intermediate Ca2+ concentrations can lead to switching from the UP to the DOWN state (similar to a LTD event). This can be achieved if protein phosphatase activity promoting CaMKII dephosphorylation activates at lower Ca2+ levels than kinase activity. Finally, it is shown that the CaMKII system can qualitatively reproduce results of plasticity outcomes in response to spike-timing dependent plasticity (STDP) and presynaptic stimulation protocols. This shows that the CaMKII protein network can account for both induction, through LTP/LTD-like transitions, and storage, due to its bistability, of synaptic changes. Learning and memory have been hypothesized to occur thanks to synaptic modifications. The efficacy of synaptic transmission has been shown to change as a function of correlated activity between presynaptic and postsynaptic neurons. Long-lasting synaptic modifications can occur in both directions (long-term potentiation (LTP) and long-term depression (LTD)). Recent experiments suggest that these synaptic changes are all-or-none switch-like changes. This would mean that only two stable states of synaptic transmission efficacy exist, i.e., a low state, or “switched off”, and a high state, or “switched on”. LTP would correspond to switching on the synapse and LTD to switching off. We propose a realistic biochemical model of protein–protein interactions which exhibits two stable states. We then investigate conditions under which the model exhibits transitions between the two stable states. We show that experimental stimulation protocols known to evoke LTP and LTD lead to corresponding transitions in the model. This work supports the idea that the investigated intracellular protein network has a role in both induction and storage of synaptic changes, and hence in learning and memory storage.
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DOI：
10.1073/pnas.89.10.4363
发表时间：
1992-05-15
影响因子：
11.1
作者：
DUDEK, SM;BEAR, MF
通讯作者：
BEAR, MF
影响因子：
56.9
作者：
De Koninck, P;Schulman, H
通讯作者：
Schulman, H
影响因子：
64.8
作者：
Bell, CC;Han, VZ;Grant, K
通讯作者：
Grant, K
影响因子：
5.3
作者：
Bender, VA;Bender, KJ;Feldman, DE
通讯作者：
Feldman, DE
DOI：
10.1073/pnas.96.6.3269
发表时间：
1999-03-16
影响因子：
11.1
作者：
Derkach, V;Barria, A;Soderling, TR
通讯作者：
Soderling, TR