Causes and Consequences of Hyperexcitation in Central Clock Neurons

Hyperexcited states, including depolarization block and depolarized low amplitude membrane oscillations (DLAMOs), have been observed in neurons of the suprachiasmatic nuclei (SCN), the site of the central mammalian circadian (∼24-hour) clock. The causes and consequences of this hyperexcitation have not yet been determined. Here, we explore how individual ionic currents contribute to these hyperexcited states, and how hyperexcitation can then influence molecular circadian timekeeping within SCN neurons. We developed a mathematical model of the electrical activity of SCN neurons, and experimentally verified its prediction that DLAMOs depend on post-synaptic L-type calcium current. The model predicts that hyperexcited states cause high intracellular calcium concentrations, which could trigger transcription of clock genes. The model also predicts that circadian control of certain ionic currents can induce hyperexcited states. Putting it all together into an integrative model, we show how membrane potential and calcium concentration provide a fast feedback that can enhance rhythmicity of the intracellular circadian clock. This work puts forward a novel role for electrical activity in circadian timekeeping, and suggests that hyperexcited states provide a general mechanism for linking membrane electrical dynamics to transcription activation in the nucleus.在哺乳动物中枢近日节律（约24小时）时钟所在的视交叉上核（suprachiasmatic nuclei, SCN）神经元中，已观测到过度兴奋状态，包括去极化阻滞与去极化低振幅膜振荡（depolarized low amplitude membrane oscillations, DLAMOs）。目前该类过度兴奋的诱因与结果尚未明确。本研究探究了单一离子电流如何介导此类过度兴奋状态，以及过度兴奋又可如何影响视交叉上核神经元内的分子节律计时过程。我们构建了视交叉上核神经元电活动的数学模型，并通过实验验证了DLAMOs依赖于突触后L型钙电流这一模型预测。该模型显示，过度兴奋状态会导致细胞内钙浓度升高，而这一变化可触发节律基因的转录；同时模型还预测，对部分离子电流的节律调控可诱发过度兴奋状态。将上述结论整合为整合模型后，我们阐明了膜电位与钙浓度如何通过快速反馈机制增强细胞近日节律时钟的节律性。本研究提出了电活动在节律计时中的全新作用，并表明过度兴奋状态可作为连接细胞膜电动态与细胞核内转录激活的通用机制。