Pang Ji-Jie, Frankfort Benjamin J, Gross Ronald L, Wu Samuel M
Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030.
Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030
Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2593-8. doi: 10.1073/pnas.1419921112. Epub 2015 Feb 9.
Glaucoma is the second leading cause of blindness in the United States and the world, characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs in sectored patterns. Recent evidence has suggested that this early sensitivity loss may be associated with dysfunctions in the inner retina, but detailed cellular and synaptic mechanisms underlying such sensitivity changes are largely unknown. In this study, we use whole-cell voltage-clamp techniques to analyze light responses of individual bipolar cells (BCs), AII amacrine cells (AIIACs), and ON and sustained OFF alpha-ganglion cells (ONαGCs and sOFFαGCs) in dark-adapted mouse retinas with elevated intraocular pressure (IOP). We present evidence showing that elevated IOP suppresses the rod ON BC inputs to AIIACs, resulting in less sensitive AIIACs, which alter AIIAC inputs to ONαGCs via the AIIAC→cone ON BC→ONαGC pathway, resulting in lower ONαGC sensitivity. The altered AIIAC response also reduces sOFFαGC sensitivity via the AIIAC→sOFFαGC chemical synapses. These sensitivity decreases in αGCs and AIIACs were found in mice with elevated IOP for 3-7 wk, a stage when little RGC or optic nerve degeneration was observed. Our finding that elevated IOP alters neuronal function in the inner retina before irreversible structural damage occurs provides useful information for developing new diagnostic tools and treatments for glaucoma in human patients.
青光眼是美国和全球第二大致盲原因，其特征是视神经和视网膜神经节细胞（RGCs）进行性退化。青光眼患者早期表现为视网膜敏感性弥漫性丧失，随后RGCs呈扇形局灶性丧失。最近的证据表明，这种早期敏感性丧失可能与视网膜内层功能障碍有关，但这种敏感性变化背后详细的细胞和突触机制在很大程度上尚不清楚。在本研究中，我们使用全细胞电压钳技术分析了暗适应的高眼压小鼠视网膜中单个双极细胞（BCs）、AII无长突细胞（AIIACs）以及ON和持续型OFFα-神经节细胞（ONαGCs和sOFFαGCs）的光反应。我们提供的证据表明，高眼压会抑制杆状细胞ON BC对AIIACs的输入，导致AIIACs敏感性降低，这通过AIIAC→视锥细胞ON BC→ONαGC途径改变了AIIACs对ONαGCs的输入，导致ONαGCs敏感性降低。AIIAC反应的改变还通过AIIAC→sOFFαGC化学突触降低了sOFFαGCs的敏感性。在高眼压3 - 7周的小鼠中发现了αGCs和AIIACs的这些敏感性降低，这一阶段几乎未观察到RGC或视神经退化。我们的发现，即在不可逆的结构损伤发生之前，高眼压会改变视网膜内层的神经元功能，为开发针对人类青光眼患者的新诊断工具和治疗方法提供了有用信息。
