Genocchi Barbara, Cunha Andre, Jain Soumil, Hyttinen Jari, Lenk Kerstin, Ellingsrud Ada Johanne
Annu Int Conf IEEE Eng Med Biol Soc. 2020 Jul;2020:2491-2495. doi: 10.1109/EMBC44109.2020.9175306.
Cortical spreading depression (CSD) is a slowly propagating wave of depolarization of brain cells, followed by temporary silenced electrical brain activity. Major structural changes during CSD are linked to neuronal and possibly glial swelling. However, basic questions still remain unanswered. In particular, there are open questions regarding whether neurons or glial cells swell more, and how the cellular swelling affects the CSD wave propagation.In this study, we computationally explore how different parameters affect the swelling of neurons and astrocytes (starshaped glial cells) during CSD and how the cell swelling alters the CSD wave spatial distribution. We apply a homogenized mathematical model that describes electrodiffusion in the intraand extracellular space, and discretize the equations using a finite element method. The simulations are run with a twocompartment (extracellular space and neurons) and a threecompartment version of the model with astrocytes added. We consider cell swelling during CSD in four scenarios: (A) incorporating aquaporin-4 channels in the astrocytic membrane, (B) increasing the neuron/astrocyte ratio to 2:1, (C) blocking and increasing the Na/K-ATPase rate in the astrocytic compartment, and (D) blocking the Cl channels in astrocytes. Our results show that increasing the water permeability in the astrocytes results in a higher astrocytic swelling and a lower neuronal swelling than in the default case. Further, elevated neuronal density increases the swelling in both neurons and astrocytes. Blocking the Na/K-ATPase in the astrocytes leads to an increased wave width and swelling in both compartments, which instead decreases when the pump rate is raised. Blocking the Cl channels in the astrocytes results in neuronal swelling, and a shrinkage in the astrocytes. Our results suggest a supporting role of astrocytes in preventing cellular swelling and CSD, as well as highlighting how dysfunctions in astrocytes might elicit CSD.
皮层扩散性抑制（CSD）是一种脑细胞去极化的缓慢传播波，随后是大脑电活动的暂时沉默。CSD期间的主要结构变化与神经元以及可能的胶质细胞肿胀有关。然而，一些基本问题仍然没有答案。特别是，关于神经元或胶质细胞哪个肿胀得更多，以及细胞肿胀如何影响CSD波的传播，仍存在悬而未决的问题。在本研究中，我们通过计算探索不同参数如何影响CSD期间神经元和星形胶质细胞（星形胶质细胞）的肿胀，以及细胞肿胀如何改变CSD波的空间分布。我们应用一个均匀化的数学模型来描述细胞内和细胞外空间的电扩散，并使用有限元方法对方程进行离散化。模拟运行采用双室模型（细胞外空间和神经元）以及添加了星形胶质细胞的三室模型。我们考虑了CSD期间细胞肿胀的四种情况：（A）在星形胶质细胞膜中纳入水通道蛋白-4通道，（B）将神经元/星形胶质细胞比例增加到2:1，（C）阻断并增加星形胶质细胞区室中的钠钾ATP酶速率，以及（D）阻断星形胶质细胞中的氯通道。我们的结果表明，与默认情况相比，增加星形胶质细胞的水渗透性会导致更高的星形胶质细胞肿胀和更低的神经元肿胀。此外，神经元密度升高会增加神经元和星形胶质细胞的肿胀。阻断星形胶质细胞中的钠钾ATP酶会导致两个区室的波宽增加和肿胀，而当泵速率提高时，肿胀反而会减少。阻断星形胶质细胞中的氯通道会导致神经元肿胀，而星形胶质细胞会收缩。我们的结果表明星形胶质细胞在预防细胞肿胀和CSD方面具有支持作用，同时也突出了星形胶质细胞功能障碍可能引发CSD的方式。
