The Vanderbilt Eye Institute, Nashville, TN, USA; Vanderbilt Vision Research Center, Vanderbilt University Medical Center, 1161 21st Ave S, AA7100 Medical Center North Nashville, Tennessee, 37232, USA.
Prog Retin Eye Res. 2021 Sep;84:100953. doi: 10.1016/j.preteyeres.2021.100953. Epub 2021 Feb 25.
Glaucoma causes loss of vision through degeneration of the retinal ganglion cell (RGC) projection to the brain. The disease is characterized by sensitivity to intraocular pressure (IOP) conveyed at the optic nerve head, through which RGC axons pass unmyelinated to form the optic nerve. From this point, a pathogenic triumvirate comprising inflammatory, oxidative, and metabolic stress influence both proximal structures in the retina and distal structures in the optic projection. This review focuses on metabolic stress and how the optic projection may compensate through novel adaptive mechanisms to protect excitatory signaling to the brain. In the retina and proximal nerve head, the unmyelinated RGC axon segment is energy-inefficient, which leads to increased demand for adenosine-5'-triphosphate (ATP) at the risk of vulnerability to Ca-related metabolic and oxidative pressure. This vulnerability may underlie the bidirectional nature of progression. However, recent evidence highlights that the optic projection in glaucoma is not passive but rather demonstrates adaptive processes that may push back against neurodegeneration. In the retina, even as synaptic and dendritic pruning ensues, early progression involves enhanced excitability of RGCs. Enhancement involves depolarization of the resting membrane potential and increased response to light, independent of RGC morphological type. This response is axogenic, arising from increased levels and translocation of voltage-gated sodium channels (NaV) in the unmyelinated segment. During this same early period, large-scale networks of gap-junction coupled astrocytes redistribute metabolic resources to the optic projection stressed by elevated IOP to slow loss of axon function. This redistribution may reflect more local remodeling, as astrocyte processes respond to focal metabolic duress by boosting glycogen turnover in response to axonal activity in an effort to promote survival of the healthiest axons. Both enhanced excitability and metabolic redistribution are transient, indicating that the same adaptive mechanisms that apparently serve to slow progression ultimately may be too expensive for the system to sustain over longer periods.
青光眼通过视网膜神经节细胞（RGC）向大脑的投射退化导致视力丧失。该疾病的特征是对通过无髓 RGC 轴突传递的视神经头部的眼内压（IOP）敏感，这些轴突无髓形成视神经。从这一点出发，炎症、氧化和代谢应激的致病三联体影响视网膜的近端结构和视神经投射的远端结构。这篇综述重点介绍了代谢应激以及视神经投射如何通过新的适应机制来保护向大脑的兴奋信号传递。在视网膜和近端神经头部，无髓 RGC 轴突段能量效率低下，这导致对三磷酸腺苷（ATP）的需求增加，从而增加了对 Ca 相关代谢和氧化压力的脆弱性。这种脆弱性可能是进展的双向性质的基础。然而，最近的证据强调，青光眼的视神经投射不是被动的，而是表现出适应性过程，可能会阻止神经退行性变。在视网膜中，即使发生突触和树突修剪，早期进展也涉及 RGC 兴奋性增强。增强涉及静息膜电位去极化和对光的反应增加，与 RGC 形态类型无关。这种反应是轴源性的，源自无髓段电压门控钠通道（NaV）水平升高和易位。在同一早期阶段，缝隙连接偶联星形胶质细胞的大规模网络将代谢资源重新分配到因 IOP 升高而受到压力的视神经投射中，以减缓轴突功能的丧失。这种再分配可能反映了更多的局部重塑，因为星形胶质细胞过程通过响应轴突活动来增加糖原周转率来响应局部代谢应激，以促进最健康轴突的存活。兴奋性增强和代谢再分配都是短暂的，这表明，尽管明显有助于减缓进展的相同适应机制最终可能对系统来说过于昂贵，无法维持更长时间。
