Kim Taegon, Tanaka-Yamamoto Keiko
Center for Functional Connectomics, Korea Institute of Science and Technology (KIST), Seoul, South Korea.
Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea.
Front Cell Neurosci. 2019 Feb 26;13:72. doi: 10.3389/fncel.2019.00072. eCollection 2019.
Neurons undergo dynamic processes of constitutive AMPA-type glutamate receptor (AMPAR) trafficking, such as the insertion and internalization of AMPARs by exocytosis and endocytosis, while stably maintaining synaptic efficacy. Studies using advanced imaging techniques have suggested that the frequency of these constitutive trafficking processes, as well as the number of AMPARs that are involved in a particular event highly fluctuate. In addition, mechanisms that trigger some forms of synaptic plasticity have been shown to include not only these processes but also additional fluctuating processes, such as the sorting of AMPARs to late endosomes (LEs). Thus, the regulation of postsynaptic AMPARs by the endosomal trafficking system appears to have superficially conflicting properties between the stability or organized control of plasticity and highly fluctuating or stochastic processes. However, it is not clear how the endosomal trafficking system reconciles and utilizes such conflicting properties. Although deterministic models have been effective to describe the stable maintenance of synaptic AMPAR numbers by constitutive recycling, as well as the involvement of endosomal trafficking in synaptic plasticity, they do not take stochasticity into account. In this study, we introduced the stochasticity into the model of each crucial machinery of the endosomal trafficking system. The specific questions we solved by our improved model are whether stability is accomplished even with a combination of fluctuating processes, and how overall variability occurs while controlling long-term synaptic depression (LTD). Our new stochastic model indeed demonstrated the stable regulation of postsynaptic AMPAR numbers at the basal state and during LTD maintenance, despite fast fluctuations in AMPAR numbers as well as high variability in the time course and amounts of LTD. In addition, our analysis suggested that the high variability arising from this stochasticity is beneficial for reproducing the relatively constant timing of LE sorting for LTD. We therefore propose that the coexistence of stability and stochasticity in the endosomal trafficking system is suitable for stable synaptic transmission and the reliable induction of synaptic plasticity, with variable properties that have been observed experimentally.
神经元经历组成型AMPA型谷氨酸受体（AMPAR）转运的动态过程，例如通过胞吐作用和内吞作用实现AMPAR的插入和内化，同时稳定维持突触效能。使用先进成像技术的研究表明，这些组成型转运过程的频率以及参与特定事件的AMPAR数量高度波动。此外，已表明触发某些形式突触可塑性的机制不仅包括这些过程，还包括其他波动过程，例如将AMPAR分选到晚期内体（LE）。因此，内体转运系统对突触后AMPAR的调节在可塑性的稳定性或有组织的控制与高度波动或随机过程之间似乎具有表面上相互矛盾的特性。然而，尚不清楚内体转运系统如何协调和利用这些相互矛盾的特性。尽管确定性模型已有效地描述了通过组成型循环对突触AMPAR数量的稳定维持以及内体转运在突触可塑性中的作用，但它们没有考虑到随机性。在本研究中，我们将随机性引入内体转运系统每个关键机制的模型中。我们通过改进模型解决的具体问题是，即使存在波动过程的组合，稳定性是否仍能实现，以及在控制长期突触抑制（LTD）时整体变异性是如何产生的。我们的新随机模型确实表明，尽管AMPAR数量快速波动以及LTD的时间进程和量具有高变异性，但在基础状态和LTD维持期间突触后AMPAR数量仍受到稳定调节。此外，我们的分析表明，这种随机性产生的高变异性有利于再现LTD的LE分选相对恒定的时间。因此，我们提出内体转运系统中稳定性和随机性的共存适合于稳定的突触传递和可靠的突触可塑性诱导，具有实验中观察到的可变特性。
