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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus.
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Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus.

机译：血管周围水通道蛋白4的丧失可能是人类致癫痫海马体缺水和K +稳态的基础。

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摘要

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.
机译：颞叶内侧颞叶癫痫（MTLE）和海马硬化患者的癫痫发作与大脑中细胞外K +的异常积累有关。实验研究表明，去除水通道水通道水通道蛋白4（AQP4）的血管周池会损害细胞外K +的清除，这表明K +的有效清除取决于伴随的穿过星形胶质细胞膜的水通量。因此，我们假设血管周围AQP4的丢失可能与MTLE的发病机制有关。蛋白质印迹分析显示，与非MTLE海马相比，MTLE中AQP4的总体水平有所提高，而定量ImmunoGold电子显微镜检查显示，沿星形胶质细胞血管周膜结构域的AQP4密度在MTLE的CA1区域比非MTLE的降低了44％。 -MTLE海马。面对神经纤维的星形胶质细胞膜上AQP4的密度没有差异。由于将AQP4锚定在血管周星形胶质细胞足底膜上取决于肌营养不良蛋白复合物，因此通过免疫组织化学评估了肌营养不良蛋白的71 kDa脑特异性同工型的定位。在非MTLE海马中，肌营养不良蛋白优先定位在血管附近。然而，在MTLE海马中，硬化区域不存在血管周肌营养不良蛋白，这表明血管周AQP4的丧失是肌营养不良蛋白复合物破坏的继发因素。我们推测，MTLE中血管周围AQP4的丢失很可能会导致水流过星形胶质细胞的扰动，从而导致胞外K +的缓冲作用减弱和癫痫发作倾向增加。

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