Gliotoxin-induced swelling of astrocytes hinders diffusion in brain extracellular space via formation of dead-space microdomains.
Gliotoxin-induced swelling of astrocytes hinders diffusion in brain extracellular space via formation of dead-space microdomains.
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DOI：
10.1002/glia.22661
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发表时间：
2014-07
期刊：
影响因子：
6.2
通讯作者：
Hrabetova, Sabina
中科院分区：
文献类型：
--
作者：
Sherpa, Ang Doma;van de Nes, Paula;Xiao, Fanrong;Weedon, Jeremy;Hrabetova, Sabina
许多危及生命和使人衰弱的脑部疾病的特征之一是细胞肿胀，这会对细胞外空间 (ECS) 结构产生负面影响。 ECS结构由两个宏观参数决定，即曲折度（λ）和体积分数（α）。弯曲度表示与无障碍介质相比，组织对扩散分子施加的障碍。体积分数是ECS占据的组织体积的比例。从临床角度来看，有必要认识哪些因素决定 ECS 参数以及这些因素在脑部疾病中如何变化。先前的研究表明，死腔（DS）微区在缺血和低渗应激期间增加了 λ，因为这些袋状结构短暂地捕获了扩散分子。我们假设星形胶质细胞在 DS 微区的形成中发挥关键作用，因为它们的薄突具有凹形形状，当星形胶质细胞在这些病理中膨胀时，这些凹形形状可能会伸长。在这里，我们用胶质毒素 DL-α-氨基己二酸 (DL-AA) 选择性地膨胀大鼠脑切片体感新皮质中的星形胶质细胞，并使用综合光学成像 (IOI) 和实时离子电渗 (RTI) 扩散方法量化 ECS 参数。我们发现在 DL-AA 应用过程中 α 减少，λ 增加。在恢复过程中，α 恢复，而 λ 保持升高。星形胶质细胞肿胀和恢复期间 λ 的增加与 DS 微区的形成一致。我们的数据归因于星形胶质细胞在确定 ECS 参数中的重要作用，并表明细胞外扩散不仅可以通过减少肿胀而且可以通过破坏 DS 微域来改善。
One of the hallmarks of numerous life-threatening and debilitating brain diseases is cellular swelling that negatively impacts extracellular space (ECS) structure. The ECS structure is determined by two macroscopic parameters, namely tortuosity (λ) and volume fraction (α). Tortuosity represents hindrance imposed on the diffusing molecules by the tissue in comparison with an obstacle-free medium. Volume fraction is the proportion of tissue volume occupied by the ECS. From a clinical perspective, it is essential to recognize which factors determine the ECS parameters and how these factors change in brain diseases. Previous studies demonstrated that dead-space (DS) microdomains increased λ during ischemia and hypotonic stress, as these pocket-like structures transiently trapped diffusing molecules. We hypothesize that astrocytes play a key role in the formation of DS microdomains because their thin processes have concave shapes that may elongate as astrocytes swell in these pathologies. Here we selectively swelled astrocytes in the somatosensory neocortex of rat brain slices with a gliotoxin DL-α-Aminoadipic Acid (DL-AA), and we quantified the ECS parameters using Integrative Optical Imaging (IOI) and Real-Time Iontophoretic (RTI) diffusion methods. We found that α decreased and λ increased during DL-AA application. During recovery, α was restored whereas λ remained elevated. Increase in λ during astrocytic swelling and recovery is consistent with the formation of DS microdomains. Our data attribute to the astrocytes an important role in determining the ECS parameters, and indicate that extracellular diffusion can be improved not only by reducing the swelling but also by disrupting the DS microdomains.
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影响因子：
3
作者：
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通讯作者：
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影响因子：
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作者：
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