Hübel Niklas, Schöll Eckehard, Dahlem Markus A
Department of Theoretical Physics, Technische Universität Berlin, Berlin, Germany.
Department of Physics, Humboldt Universität zu Berlin, Berlin, Germany.
PLoS Comput Biol. 2014 May 1;10(5):e1003551. doi: 10.1371/journal.pcbi.1003551. eCollection 2014 May.
When neurons fire action potentials, dissipation of free energy is usually not directly considered, because the change in free energy is often negligible compared to the immense reservoir stored in neural transmembrane ion gradients and the long-term energy requirements are met through chemical energy, i.e., metabolism. However, these gradients can temporarily nearly vanish in neurological diseases, such as migraine and stroke, and in traumatic brain injury from concussions to severe injuries. We study biophysical neuron models based on the Hodgkin-Huxley (HH) formalism extended to include time-dependent ion concentrations inside and outside the cell and metabolic energy-driven pumps. We reveal the basic mechanism of a state of free energy-starvation (FES) with bifurcation analyses showing that ion dynamics is for a large range of pump rates bistable without contact to an ion bath. This is interpreted as a threshold reduction of a new fundamental mechanism of ionic excitability that causes a long-lasting but transient FES as observed in pathological states. We can in particular conclude that a coupling of extracellular ion concentrations to a large glial-vascular bath can take a role as an inhibitory mechanism crucial in ion homeostasis, while the Na⁺/K⁺ pumps alone are insufficient to recover from FES. Our results provide the missing link between the HH formalism and activator-inhibitor models that have been successfully used for modeling migraine phenotypes, and therefore will allow us to validate the hypothesis that migraine symptoms are explained by disturbed function in ion channel subunits, Na⁺/K⁺ pumps, and other proteins that regulate ion homeostasis.
当神经元发放动作电位时，通常不会直接考虑自由能的耗散，因为与储存在神经跨膜离子梯度中的巨大能量储备相比，自由能的变化往往可以忽略不计，并且长期的能量需求是通过化学能即新陈代谢来满足的。然而，在偏头痛和中风等神经系统疾病以及从脑震荡到严重损伤的创伤性脑损伤中，这些梯度可能会暂时几乎消失。我们研究基于霍奇金 - 赫胥黎（HH）形式主义扩展的生物物理神经元模型，该模型包括细胞内外随时间变化的离子浓度以及代谢能量驱动的泵。我们通过分岔分析揭示了自由能饥饿（FES）状态的基本机制，结果表明在很大范围的泵浦速率下，离子动力学是双稳态的，且不与离子浴接触。这被解释为离子兴奋性新基本机制的阈值降低，这种机制会导致在病理状态下观察到的持久但短暂的FES。我们尤其可以得出结论，细胞外离子浓度与大的神经胶质 - 血管浴的耦合可以作为离子稳态中至关重要的抑制机制发挥作用，而仅靠Na⁺/K⁺泵不足以从FES中恢复。我们的结果提供了HH形式主义与已成功用于偏头痛表型建模的激活剂 - 抑制剂模型之间缺失的联系，因此将使我们能够验证偏头痛症状是由离子通道亚基、Na⁺/K⁺泵以及其他调节离子稳态的蛋白质功能紊乱所解释的这一假设。
