在国家 “973”、国家自然科学基金和上海市基础研究重点课题资助下，复旦大学脑科学研究院、复旦大学附属眼耳鼻喉科医院王中峰教授、孙兴怀教授、杨雄里院士率领的视网膜研究团队发现青光眼视网膜胶质细胞激活新机制，为临床上防止青光眼恶化，以及有效阻止青光眼所导致的视网膜神经细胞的死亡（失明）提供了新的理论依据。该成果已刊登在最新一期的国际神经科学著名期刊《神经科学杂志》上。
青光眼是由于视网膜神经节细胞损伤、不可逆性视功能损害疾病，已成为世界上第二大致盲性眼病，其临床症状主要是“高眼压”引起的眼睛不同程度的疼痛。研究发现青光眼所导致的失明，与视网膜胶质细胞被激活密切相关，几乎所有患有神经系统（包括视网膜）损伤疾病的患者都伴随有胶质细胞“被激活”现象，该激活机制在青光眼神经节细胞损伤中究竟如何扮演 “破坏性角色”，如何使胶质细胞“不被激活”，一直是各国科学家探讨和研究的重大课题。
为破解这一重大课题，王中峰教授、孙兴怀教授、杨雄里院士率领博士研究生季敏、苗艳颖等，利用老鼠建立“高眼压模型”来模拟人的青光眼疾病，研究后发现，“高眼压”导致视网膜内一种叫“穆勒”的主要胶质细胞被激活了。后来，他们又通过在眼睛的玻璃体内注射特异性的药物的方法，结果发现青光眼会导致视网膜内一种作为细胞之间“光信号传递”的氨基酸使谷氨酸的量增多，增多的谷氨酸会与胶质细胞膜上的一种称为“受体”的蛋白质结合，然后通过细胞内一系列的反应，结果使胶质细胞膜上的一种能够通透钾离子的蛋白质的量变少了，正是这种蛋白质量的减少，最后导致胶质细胞被激活。而激活的胶质细胞会释放出许多有害物质，引起视网膜的神经细胞大量死亡，最终导致失明。（生物谷Bioon.com）
doi:10.1523/JNEUROSCI.1291-12.2012
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Group I mGluR-Mediated Inhibition of Kir Channels Contributes to Retinal Müller Cell Gliosis in a Rat Chronic Ocular Hypertension Model
Min Ji, Yanying Miao, Ling-Dan Dong, Jie Chen, Xiao-Fen Mo, Shi-Xiang Jiang, Xing-Huai Sun, Xiong-Li Yang, and Zhongfeng Wang
Müller cell gliosis, which is characterized by upregulated expression of glial fibrillary acidic protein (GFAP), is a universal response in many retinal pathological conditions. Whether down-regulation of inward rectifying K(+) (Kir) channels, which commonly accompanies the enhanced GFAP expression, could contribute to Müller cell gliosis is poorly understood. We investigated changes of Kir currents, GFAP and Kir4.1 protein expression in Müller cells in a rat chronic ocular hypertension (COH) model, and explored the mechanisms underlying Müller cell gliosis. We show that Kir currents and Kir4.1 protein expression in Müller cells were reduced significantly, while GFAP expression was increased in COH rats, and these changes were eliminated by MPEP, a group I metabotropic glutamate receptors (mGluR I) subtype mGluR5 antagonist. In normal isolated Müller cells, the mGluR I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) suppressed the Kir currents and the suppression was blocked by MPEP. The DHPG effect was mediated by the intracellular Ca(2+)-dependent PLC/IP(3)-ryanodine/PKC signaling pathway, but the cAMP-PKA pathway was not involved. Moreover, intravitreal injection of DHPG in normal rats induced changes in Müller cells, similar to those observed in COH rats. The DHPG-induced increase of GFAP expression in Müller cells was obstructed by Ba(2+), suggesting the involvement of Kir channels. We conclude that overactivation of mGluR5 by excessive extracellular glutamate in COH rats could contribute to Müller cell gliosis by suppressing Kir channels.
