Hendrickson Eric B, Edgerton Jeremy R, Jaeger Dieter
Biomedical Engineering Department, Georgia Institute of Technology, Atlanta, GA 30332, USA.
J Comput Neurosci. 2011 Oct;31(2):329-46. doi: 10.1007/s10827-010-0312-x. Epub 2011 Jan 18.
The voltage and time dependence of ion channels can be regulated, notably by phosphorylation, interaction with phospholipids, and binding to auxiliary subunits. Many parameter variation studies have set conductance densities free while leaving kinetic channel properties fixed as the experimental constraints on the latter are usually better than on the former. Because individual cells can tightly regulate their ion channel properties, we suggest that kinetic parameters may be profitably set free during model optimization in order to both improve matches to data and refine kinetic parameters. To this end, we analyzed the parameter optimization of reduced models of three electrophysiologically characterized and morphologically reconstructed globus pallidus neurons. We performed two automated searches with different types of free parameters. First, conductance density parameters were set free. Even the best resulting models exhibited unavoidable problems which were due to limitations in our channel kinetics. We next set channel kinetics free for the optimized density matches and obtained significantly improved model performance. Some kinetic parameters consistently shifted to similar new values in multiple runs across three models, suggesting the possibility for tailored improvements to channel models. These results suggest that optimized channel kinetics can improve model matches to experimental voltage traces, particularly for channels characterized under different experimental conditions than recorded data to be matched by a model. The resulting shifts in channel kinetics from the original template provide valuable guidance for future experimental efforts to determine the detailed kinetics of channel isoforms and possible modulated states in particular types of neurons.
离子通道的电压和时间依赖性可受到调节，尤其是通过磷酸化、与磷脂的相互作用以及与辅助亚基的结合。许多参数变化研究在保持通道动力学特性固定的同时放开了电导密度，因为对后者的实验约束通常比对前者的更好。由于单个细胞能够严格调节其离子通道特性，我们建议在模型优化过程中可放开动力学参数，以便既能改善与数据的匹配度，又能细化动力学参数。为此，我们分析了三个经电生理特征化和形态学重建的苍白球神经元简化模型的参数优化。我们针对不同类型的自由参数进行了两次自动搜索。首先，放开电导密度参数。即便最终得到的最佳模型也表现出不可避免的问题，这些问题归因于我们在通道动力学方面的局限性。接下来，我们针对优化后的密度匹配放开通道动力学参数，从而显著提高了模型性能。在跨越三个模型的多次运行中，一些动力学参数持续转向相似的新值，这表明对通道模型进行针对性改进具有可能性。这些结果表明，优化后的通道动力学能够改善模型与实验电压轨迹的匹配度，特别是对于那些在与模型要匹配的记录数据不同的实验条件下所表征的通道。通道动力学相对于原始模板的最终变化为未来实验工作提供了有价值的指导，这些实验旨在确定特定类型神经元中通道亚型的详细动力学以及可能的调节状态。
