Potassium and sodium microdomains in thin astroglial processes: A computational model study.
Potassium and sodium microdomains in thin astroglial processes: A computational model study.
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DOI：
10.1371/journal.pcbi.1006151
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发表时间：
2018-05
影响因子：
4.3
通讯作者：
McDaid L
中科院分区：
文献类型：
--
作者：
Breslin K;Wade JJ;Wong-Lin K;Harkin J;Flanagan B;Van Zalinge H;Hall S;Walker M;Verkhratsky A;McDaid L
捕捉突触周围摇篮(PSC)离子分子内稳态控制的生物物理模型对于理解星形胶质细胞和神经元之间的相互作用具有重要意义。在本文中，我们发展了一个多室数学模型，它提出了一种新的机制，在薄过程中，由于带负电荷的膜脂导致在偶极头部附近形成深势垒，从而限制了离子在薄过程中的流动。这些井将阳离子的流动限制为在相邻的井之间“跳跃”，因为它们横跨整个过程，这种阳离子的表面保留将导致在PSC形成钾(K+)和钠(Na+)微区。我们进一步提出，在PSC处形成的K+微域，为K+返回到细胞外空间被神经元摄取提供驱动力，从而防止K+下射。在谷氨酸刺激一段时间后，我们的模拟中也观察到了Na+的缓慢衰减，这与实验观察到的结果非常一致。文中还讨论了神经元兴奋过程中微区形成的病理学意义。在神经元活动期间，周围细胞外间隙(ECS)的离子动态平衡被破坏。为了为持续的神经元功能提供一个健康的环境，必须缓冲多余的离子，如钾，使其远离ECS；这是星形胶质细胞提供的一个重要的支持作用。长期以来，人们一直认为，星形胶质细胞不仅从ECS中清除离子，还将它们输送到大脑中浓度较低的其他区域。然而，虽然我们的计算模型模拟同意星形胶质细胞确实从ECS中移除了这些离子，但它们也表明这些离子主要存储在PSC的本地并返回到ECS，从而恢复了离子的动态平衡。此外，我们在这篇文章中详细说明，这种情况的发生是因为以前被忽视的生物物理现象，这种现象只在薄薄的星形胶质细胞突起中占主导地位。这些阳离子在薄过程中的流动主要是通过表面传导，在那里它们在膜内表面经历固定负电荷的吸引。这种负电荷限制了阳离子沿表面的运动，因此它们的流速也受到了限制。因此，由于PSC和星形胶质细胞胞体之间的低电导通路，在神经元兴奋过程中释放的钾等离子进入PSC并被局部储存。我们的模拟还表明，在神经元活动消失后，这种局部K+的积聚返回到ECS，这可能解释了为什么没有观察到K+欠冲；这一结果与实验观察一致。此外，同样的机制也可以解释Na+离子的瞬变行为，在薄的过程中，实验上观察到了一个缓慢的衰减时间常数。这些发现对星形胶质细胞在生理和病理条件下调节神经元兴奋性的作用具有重要的意义，从而突出了本文工作的意义。
A biophysical model that captures molecular homeostatic control of ions at the perisynaptic cradle (PsC) is of fundamental importance for understanding the interplay between astroglial and neuronal compartments. In this paper, we develop a multi-compartmental mathematical model which proposes a novel mechanism whereby the flow of cations in thin processes is restricted due to negatively charged membrane lipids which result in the formation of deep potential wells near the dipole heads. These wells restrict the flow of cations to “hopping” between adjacent wells as they transverse the process, and this surface retention of cations will be shown to give rise to the formation of potassium (K+) and sodium (Na+) microdomains at the PsC. We further propose that a K+ microdomain formed at the PsC, provides the driving force for the return of K+ to the extracellular space for uptake by the neurone, thereby preventing K+ undershoot. A slow decay of Na+ was also observed in our simulation after a period of glutamate stimulation which is in strong agreement with experimental observations. The pathological implications of microdomain formation during neuronal excitation are also discussed. During periods of neuronal activity, ionic homeostasis in the surrounding extracellular space (ECS) is disturbed. To provide a healthy environment for continued neuronal function, excess ions such as potassium must be buffered away from the ECS; a vital supportive role provided by astrocyte cells. It has long been thought that astrocytes not only removed ions from the ECS but also transport them to other areas of the brain where their concentrations are lower. However, while our computational model simulations agree that astrocytes do remove these ions from the ECS they also show that these ions are mainly stored locally at the PsC to be returned to the ECS, thus restoring ionic homeostasis. Furthermore, we detail in this paper that this happens because of a previously overlooked biophysical phenomenon that is only dominant in thin astrocyte processes. The flow of these cations within thin processes is primarily by surface conduction where they experience the attraction of fixed negative charge at the membrane inner surface. This negative charge constrains cation movement along the surface and so their flow rate is restricted. Consequently, ions such as potassium that are released during neuronal excitation enter the PsC and are stored locally due to the low conductance pathway between the PsC and the astrocyte soma. Our simulations also show that this local build-up of K+ is returned to the ECS after the neuronal activity dies off which could potentially explain why K+ undershoot has not been observed; this result agrees with experimental observations. Moreover, the same mechanism can also explain the transient behaviour of Na+ ions whereby in thin processes a slow decay time constant is experimentally observed. These findings have important implications for the role of astrocytes in regulating neuronal excitability under physiological and pathological conditions, and therefore highlight the significance of the work presented in this paper.
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影响因子：
12.4
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