Molecular Neuroscience Department, The Krasnow Institute for Advanced Studies, George Mason University, Fairfax, VA, USA.
Wiley Interdiscip Rev Syst Biol Med. 2013 Nov-Dec;5(6):717-31. doi: 10.1002/wsbm.1240. Epub 2013 Sep 9.
Interactions among signaling pathways that are activated by transmembrane receptors produce complex networks and emergent dynamical behaviors that are implicated in synaptic plasticity. Temporal dynamics and spatial aspects are critical determinants of cell responses such as synaptic plasticity, although the mapping between spatiotemporal activity pattern and direction of synaptic plasticity is not completely understood. Computational modeling of neuronal signaling pathways has significantly contributed to understanding signaling pathways underlying synaptic plasticity. Spatial models of signaling pathways in hippocampal neurons have revealed mechanisms underlying the spatial distribution of extracellular signal-related kinase (ERK) activation in hippocampal neurons. Other spatial models have demonstrated that the major role of anchoring proteins in striatal and hippocampal synaptic plasticity is to place molecules near their activators. Simulations of yet other models have revealed that the spatial distribution of synaptic plasticity may differ for potentiation versus depression. In general, the most significant advances have been made by interactive modeling and experiments; thus, an interdisciplinary approach should be applied to investigate critical issues in neuronal signaling pathways. These issues include identifying which transmembrane receptors are key for activating ERK in neurons, and the crucial targets of kinases that produce long-lasting synaptic plasticity. Although the number of computer programs for computationally efficient simulation of large reaction-diffusion networks is increasing, parameter estimation and sensitivity analysis in these spatial models remain more difficult than in single compartment models. Advances in live cell imaging coupled with further software development will continue to accelerate the development of spatial models of synaptic plasticity.
信号通路之间的相互作用，这些信号通路被跨膜受体激活，产生复杂的网络和涌现的动力学行为，这些行为与突触可塑性有关。尽管时空活动模式与突触可塑性方向之间的映射尚未完全理解，但时间动态和空间方面是细胞反应（如突触可塑性）的关键决定因素。神经元信号通路的计算模型对理解突触可塑性背后的信号通路有很大的贡献。海马神经元中信号通路的空间模型揭示了细胞外信号相关激酶 (ERK) 在海马神经元中激活的空间分布的机制。其他空间模型表明，锚定蛋白在纹状体和海马突触可塑性中的主要作用是将分子放置在其激活剂附近。其他模型的模拟还表明，突触可塑性的空间分布可能因增强与抑郁而不同。一般来说，通过交互式建模和实验取得了最显著的进展；因此，应该采用跨学科的方法来研究神经元信号通路中的关键问题。这些问题包括确定哪些跨膜受体是神经元中激活 ERK 的关键，以及产生长期突触可塑性的激酶的关键靶点。尽管用于有效模拟大反应扩散网络的计算机程序数量在增加，但这些空间模型中的参数估计和敏感性分析仍然比单室模型更困难。活细胞成像的进展与进一步的软件开发相结合，将继续加速突触可塑性的空间模型的发展。
