Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus
Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus
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DOI：
10.1073/pnas.0409308102
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发表时间：
2005-01-25
影响因子：
11.1
通讯作者：
de Lanerolle, NC
中科院分区：
文献类型：
--
作者：
Eid, T;Lee, TSW;de Lanerolle, NC
在内侧颞叶癫痫（MTLE）和海马硬化患者中，脑中细胞外K+的异常积累与癫痫发作的发生有关。实验研究已经表明，细胞外K+的清除受到水通道水通道蛋白4（AQP4）的血管周围池的去除的影响，这表明K+的有效清除取决于通过星形胶质细胞膜的伴随水通量。因此，我们推测血管周围AQP4的丢失可能参与了MTLE的发病机制。而Western印迹分析显示，整体增加AQP4水平在MTLE与非MTLE脑血管瘤相比，定量免疫金电子显微镜显示，AQP4的密度沿着血管周围的星形胶质细胞膜域减少了44%，在区域CA1的MTLE与非MTLE脑血管瘤。星形胶质细胞膜上的AQP4密度与神经胶质细胞表面的AQP4密度无差异。由于锚定AQP4血管周围的星形胶质细胞足膜依赖于抗肌萎缩蛋白复合物，本地化的71 kDa的脑特异性亚型抗肌萎缩蛋白进行了评估免疫组织化学。在非MTLE海马，肌营养不良蛋白优先定位于血管附近。然而，在MTLE海马，血管周围的肌营养不良蛋白是不存在的scaffolds地区，这表明血管周围的AQP4的损失是继发于肌营养不良蛋白复合物的破坏。我们推测MTLE血管周围AQP4的丢失可能导致水通过星形胶质细胞的扰动通量，导致细胞外K+缓冲受损和癫痫发作倾向增加。
An abnormal accumulation of extracellular K+ in the brain has been implicated in the generation of seizures in patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis. Experimental studies have shown that clearance of extracellular K+ is compromised by removal of the perivascular pool of the water channel aquaporin 4 (AQP4), suggesting that an efficient clearance of K+ depends on a concomitant water flux through astrocyte membranes. Therefore, we hypothesized that loss of perivascular AQP4 might be involved in the pathogenesis of MTLE. Whereas Western blot analysis showed an overall increase in AQP4 levels in MTLE compared with non-MTLE hippocampi, quantitative ImmunoGold electron microscopy revealed that the density of AQP4 along the perivascular membrane domain of astrocytes was reduced by 44% in area CA1 of MTLE vs. non-MTLE hippocampi. There was no difference in the density of AQP4 on the astrocyte membrane facing the neuropil. Because anchoring of AQP4 to the perivascular astrocyte endfoot membrane depends on the dystrophin complex, the localization of the 71-kDa brain-specific isoform of dystrophin was assessed by immunohistochemistry. In non-MTLE hippocampus, dystrophin was preferentially localized near blood vessels. However, in the MTLE hippocampus, the perivascular dystrophin was absent in sclerotic areas, suggesting that the loss of perivascular AQP4 is secondary to a disruption of the dystrophin complex. We postulate that the loss of perivascular AQP4 in MTLE is likely to result in a perturbed flux of water through astrocytes leading to an impaired buffering of extracellular K+ and an increased propensity for seizures.