Vanderbilt Eye Institute, Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, AA7103 MCN/VUIIS, 1161 21st Ave. S., Nashville, TN, 37232, USA.
Mol Neurobiol. 2022 Mar;59(3):1366-1380. doi: 10.1007/s12035-021-02675-5. Epub 2022 Jan 5.
The BCL-2 (B-cell lymphoma-2) family of proteins contributes to mitochondrial-based apoptosis in models of neurodegeneration, including glaucomatous optic neuropathy (glaucoma), which degrades the retinal ganglion cell (RGC) axonal projection to the visual brain. Glaucoma is commonly associated with increased sensitivity to intraocular pressure (IOP) and involves a proximal program that leads to RGC dendritic pruning and a distal program that underlies axonopathy in the optic projection. While genetic deletion of the Bcl2-associated X protein (Bax) prolongs RGC body survival in models of glaucoma and optic nerve trauma, axonopathy persists, thus raising the question of whether dendrites and the RGC light response are protected. Here, we used an inducible model of glaucoma in Bax mice to determine if Bax contributes to RGC dendritic degeneration. We performed whole-cell recordings and dye filling in RGCs signaling light onset (αON-Sustained) and offset (αOFF-Sustained). We recovered RGC dendritic morphologies by confocal microscopy and analyzed dendritic arbor complexity and size. Additionally, we assessed RGC axon function by measuring anterograde axon transport of cholera toxin subunit B to the superior colliculus and behavioral spatial frequency threshold (i.e., spatial acuity). We found 1 month of IOP elevation did not cause significant RGC death in either WT or Bax retinas. However, IOP elevation reduced dendritic arbor complexity of WT αON-Sustained and αOFF-Sustained RGCs. In the absence of Bax, αON- and αOFF-Sustained RGC dendritic arbors remained intact following IOP elevation. In addition to dendrites, neuroprotection by Bax generalized to αON-and αOFF-Sustained RGC light- and current-evoked responses. Both anterograde axon transport and spatial acuity declined during IOP elevation in WT and Bax mice. Collectively, our results indicate Bax contributes to RGC dendritic degeneration and distinguishes the proximal and distal neurodegenerative programs involved during the progression of glaucoma.
BCL-2（B 细胞淋巴瘤-2）家族蛋白有助于神经退行性疾病模型中的线粒体凋亡，包括青光眼性视神经病变（青光眼），它会导致视网膜神经节细胞（RGC）轴突投射到视觉大脑。青光眼通常与对眼内压（IOP）的敏感性增加有关，涉及一个近端程序，导致 RGC 树突修剪和一个远端程序，导致视神经投射中的轴突病。虽然 Bcl2 相关 X 蛋白（Bax）的基因缺失延长了青光眼和视神经损伤模型中的 RGC 体存活，但轴突病仍然存在，因此提出了树突和 RGC 光反应是否受到保护的问题。在这里，我们使用 Bax 小鼠的诱导型青光眼模型来确定 Bax 是否有助于 RGC 树突退化。我们在 Bax 小鼠中进行了全细胞记录和染料填充，以检测 RGC 对光起始（αON-Sustained）和结束（αOFF-Sustained）的信号反应。我们通过共聚焦显微镜恢复了 RGC 树突形态，并分析了树突分支复杂性和大小。此外，我们通过测量霍乱毒素亚单位 B 向上丘的顺行轴突运输以及行为空间频率阈值（即空间敏锐度）来评估 RGC 轴突功能。我们发现，IOP 升高 1 个月不会导致 WT 或 Bax 视网膜中 RGC 死亡的显著增加。然而，IOP 升高降低了 WT αON-Sustained 和 αOFF-Sustained RGC 的树突分支复杂性。在没有 Bax 的情况下，IOP 升高后，αON-和 αOFF-Sustained RGC 的树突分支仍然完整。除了树突，Bax 的神经保护作用还扩展到了 αON-和 αOFF-Sustained RGC 的光和电流诱发反应。在 WT 和 Bax 小鼠中，IOP 升高期间顺行轴突运输和空间敏锐度均下降。总的来说，我们的结果表明 Bax 有助于 RGC 树突退化，并区分了青光眼进展过程中涉及的近端和远端神经退行性程序。
