Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030;
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):8859-8864. doi: 10.1073/pnas.1706994114. Epub 2017 Jul 31.
Glaucoma is a leading cause of blindness worldwide, and is characterized by progressive retinal ganglion cell (RGC) death. An experimental model of glaucoma has been established by elevating the intraocular pressure (IOP) via microbead occlusion of ocular fluid outflow in mice. Studies in this model have found visual dysfunction that varied with adaptational state, occurred before anatomical changes, and affected OFF RGCs more than ON RGCs. These results indicate subtle alterations in the underlying retinal circuitry that could help identify disease before irreversible RGC changes. Therefore, we looked at how RGC function was altered with elevated IOP under both photopic and scotopic conditions. We first found that responses to light offset are diminished with IOP elevation along with a concomitant decrease in receptive field center size for OFF RGCs. In addition, the antagonistic surround strength and size was reduced in ON RGCs. Furthermore, elevation of IOP significantly accelerated the photopic temporal tuning of RGC center responses in both ON and OFF RGCs. We found that some of the IOP-induced functional changes to OFF RGCs relied on ON cross-over pathways, indicating dysfunction in inner retinal circuitry. Overall, these results suggest that IOP alters multiple functions in the retina depending on the adaptational state. They provide a basis for designing multiple functional tests for early detection of glaucoma and for circuit-specific therapeutic targets in treatment of this blinding disease.
青光眼是全球范围内导致失明的主要原因，其特征是视网膜神经节细胞（RGC）进行性死亡。通过微珠阻塞小鼠眼内液流出来升高眼内压（IOP），建立了青光眼的实验模型。该模型中的研究发现，视觉功能障碍随适应状态而变化，在解剖结构变化之前发生，并影响 OFF RGC 多于 ON RGC。这些结果表明，视网膜下电路存在细微变化，这可能有助于在 RGC 发生不可逆转变化之前识别疾病。因此，我们研究了在光暗两种条件下，升高 IOP 如何改变 RGC 功能。我们首先发现，随着 IOP 升高，光暗对比的反应减弱，同时 OFF RGC 感受野中心大小减小。此外，ON RGC 的拮抗环绕强度和大小减小。此外，升高 IOP 显著加速了 ON 和 OFF RGC 中心反应的明适应时程调谐。我们发现，一些 OFF RGC 的 IOP 诱导的功能变化依赖于 ON 交叉途径，表明内视网膜电路功能障碍。总的来说，这些结果表明，IOP 根据适应状态改变视网膜的多种功能。它们为设计多种功能测试提供了基础，以便早期发现青光眼，并为治疗这种致盲性疾病提供针对特定电路的治疗靶点。
