论文标题
开放钾孔驱动的神经胶质膜电压模型中的非平凡动力学
Non-trivial dynamics in a model of glial membrane voltage driven by open potassium pores
论文作者
论文摘要
尽管有分子证据表明哺乳动物星形胶质细胞接近线性稳态I-V关系反映了由多种不同调节的K+电导引起的总电流，但缺乏膜电压VM的详细ODE模型，这些模型缺乏多个电导率的膜电压VM。疾病模型中GLIA，KIR4.1中主要K+通道的不良表达的重复结果，以及它们在组装杂体KIR4.1/KIR4.1/KIR5.1通道时的纠正改变，激励我们尝试添加详细的模型，添加弱钾K2P电流，此外，除了KIR4.1，以及Kir4.1的及其他稳定状态的稳定性VR。我们询问使用kir电导率放松，名义静止状态VR保持稳定，并且在E_K之后，细胞保留了用VM的钾电极行为。 VR附近的最小二维模型表明，如果模型包含典型观察到的K+电流：KIR，K2P和非特异性钾泄漏，则Kir4.1电流的某些变化可能会导致VM多固定性。更具体地说，向外的Kir4.1电导的减少或损失引入了E_K附近的VR的不稳定性。这是通过折叠分叉发生的，从而产生了更加稳定的静止状态vdr> -10 mV。现实的时间表用于从电图癫痫发作期间的神经胶质膜上的记录来扰动膜模型。通过恒定电流通过GJC和瞬态癫痫发作的放电对扰动系统的模拟导致星形胶质细胞的去极化，并以下降 /上的状态方式在两个稳定状态之间进行了VM的切换。如果VDR附近的长时间去极化在实验上是合理的，那么这种灾难性的不稳定性将影响神经胶质功能的所有方面，从代谢支持到膜转运以及分配给Glia的所有神经调节作用。
Despite the molecular evidence that close to linear steady state I-V relationship in mammalian astrocytes reflects a total current resulting from more than one differently regulated K+ conductances, detailed ODE models of membrane voltage Vm incorporating multiple conductances are lacking. Repeated results of deregulated expressions of major K+ channels in glia, Kir4.1, in models of disease, as well as their altered rectification when assembling heteromeric Kir4.1/Kir5.1 channels have motivated us to attempt a detailed model adding the weaker potassium K2P current, in addition to Kir4.1, and study the stability of the resting state Vr. We ask whether with a deregulated Kir conductivity the nominal resting state Vr remains stable, and the cell retains a potassium electrode behavior with Vm following E_K. The minimal 2-dimensional model near Vr showed that certain alterations of Kir4.1 current may result in multistability of Vm if the model incorporates the typically observed K+ currents: Kir, K2P, and non-specific potassium leak. More specifically, a decrease or loss of outward Kir4.1 conductance introduces instability of Vr, near E_K. That happens through a fold bifurcation giving birth to a much more depolarized second, stable resting state Vdr>-10 mV. Realistic timeseries were used to perturb the membrane model, from recordings at the glial membrane during electrographic seizures. Simulations of the perturbed system by constant current through GJCs and transient seizure-like discharges as local field potentials led to depolarization of the astrocyte and switching of Vm between the two stable states, in a down-state / up-state manner. If the prolonged depolarizations near Vdr prove experimentally plausible, such catastrophic instability would impact all aspects of the glial function, from metabolic support to membrane transport and practically all neuromodulatory roles assigned to glia.
