Medical Clinic 1, Endocrinology and Diabetes, University of Luebeck, Luebeck D-23538, Germany.
Institut Computational Mathematics, Technical University Braunschweig, Braunschweig D-38106, Germany.
eNeuro. 2018 Apr 6;5(1). doi: 10.1523/ENEURO.0242-17.2018. eCollection 2018 Jan-Feb.
In cognitive memory, long-term potentiation (LTP) has been shown to occur when presynaptic and postsynaptic activities are highly correlated and glucocorticoid concentrations are in an optimal (i.e., low normal) range. In all other conditions, LTP is attenuated or even long-term depression (LTD) occurs. In this paper, we focus on NMDA receptor (NMDA-R)-dependent LTP and LTD, two processes involving various molecular mechanisms. To understand which of these mechanisms are indispensable for explaining the experimental evidence reported in the literature, we here propose a parsimonious model of NMDA-R-dependent synaptic plasticity. Central to this model are two processes. First, AMPA receptor-subunit trafficking; and second, glucocorticoid-dependent modifications of the brain-derived neurotrophic factor (BDNF)-receptor system. In 2008, we have published a core model, which contained the first process, while in the current paper we present an extended model, which also includes the second process. Using the extended model, we could show that stress attenuates LTP, while it enhances LTD. These simulation results are in agreement with experimental findings from other labs. In 2013, surprising experimental evidence showed that the GluA1 C-tail is unnecessary for LTP. When using our core model in its original form, our simulations already predicted that there would be no requirement for the GluA1 C-tail for LTP, allowing to eliminate a redundant mechanism from our model. In summary, we present a mathematical model that displays reduced complexity and is useful for explaining when and how LTP or LTD occurs at synapses during cognitive memory formation.
在认知记忆中，当突触前和突触后活动高度相关且糖皮质激素浓度处于最佳（即正常低值）范围内时，已显示长时程增强（LTP）发生。在所有其他情况下，LTP 都会减弱，甚至会发生长时程抑制（LTD）。在本文中，我们专注于 NMDA 受体（NMDA-R）依赖性 LTP 和 LTD，这两个过程涉及多种分子机制。为了了解哪些机制对于解释文献中报道的实验证据是必不可少的，我们在这里提出了一个 NMDA-R 依赖性突触可塑性的简约模型。该模型的核心是两个过程。首先，AMPA 受体亚基的转运；其次，糖皮质激素依赖性脑源性神经营养因子（BDNF）-受体系统的修饰。2008 年，我们发表了一个核心模型，其中包含了第一个过程，而在当前的论文中，我们提出了一个扩展模型，其中还包括第二个过程。使用扩展模型，我们可以证明应激会减弱 LTP，但会增强 LTD。这些模拟结果与其他实验室的实验结果一致。2013 年，令人惊讶的实验证据表明，GluA1 C 尾对于 LTP 是不必要的。当在其原始形式下使用我们的核心模型时，我们的模拟已经预测到 LTP 不需要 GluA1 C 尾，从而可以从我们的模型中消除冗余机制。总之，我们提出了一个数学模型，该模型显示出简化的复杂性，可用于解释在认知记忆形成过程中何时以及如何在突触处发生 LTP 或 LTD。
