Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06511, USA.
Cell. 2021 Aug 5;184(16):4299-4314.e12. doi: 10.1016/j.cell.2021.06.031. Epub 2021 Jul 22.
Retinal ganglion cells (RGCs) are the sole output neurons that transmit visual information from the retina to the brain. Diverse insults and pathological states cause degeneration of RGC somas and axons leading to irreversible vision loss. A fundamental question is whether manipulation of a key regulator of RGC survival can protect RGCs from diverse insults and pathological states, and ultimately preserve vision. Here, we report that CaMKII-CREB signaling is compromised after excitotoxic injury to RGC somas or optic nerve injury to RGC axons, and reactivation of this pathway robustly protects RGCs from both injuries. CaMKII activity also promotes RGC survival in the normal retina. Further, reactivation of CaMKII protects RGCs in two glaucoma models where RGCs degenerate from elevated intraocular pressure or genetic deficiency. Last, CaMKII reactivation protects long-distance RGC axon projections in vivo and preserves visual function, from the retina to the visual cortex, and visually guided behavior.
视网膜神经节细胞（RGCs）是唯一将视觉信息从视网膜传递到大脑的输出神经元。各种损伤和病理状态导致 RGC 体和轴突变性，导致不可逆转的视力丧失。一个基本的问题是，是否可以通过操纵 RGC 存活的关键调节因子来保护 RGC 免受各种损伤和病理状态的影响，并最终保护视力。在这里，我们报告说，在 RGC 体的兴奋毒性损伤或 RGC 轴突的视神经损伤后，CaMKII-CREB 信号通路受到损害，而该通路的重新激活可强烈保护 RGC 免受这两种损伤。CaMKII 活性也促进正常视网膜中的 RGC 存活。此外，CaMKII 的重新激活可保护两种青光眼模型中的 RGC，这些青光眼模型中的 RGC 因眼内压升高或遗传缺陷而变性。最后，CaMKII 的重新激活可保护体内长距离 RGC 轴突投射，并维持从视网膜到视皮层的视觉功能和视觉引导行为。
