Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (12): 2773-2780.doi: 10.4103/1673-5374.373660

Previous Articles     Next Articles

Selective deletion of zinc transporter 3 in amacrine cells promotes retinal ganglion cell survival and optic nerve regeneration after injury

Zhe Liu, Jingfei Xue, Canying Liu, Jiahui Tang, Siting Wu, Jicheng Lin, Jiaxu Han, Qi Zhang, Caiqing Wu, Haishun Huang, Ling Zhao, Yehong Zhuo*, Yiqing Li*   

  1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong Province, China
  • Online:2023-12-15 Published:2023-06-16
  • Contact: Yiqing Li, MD, PhD, liyiqing3@mail.sysu.edu.cn; Yehong Zhuo, MD, PhD, zhuoyh@mail.sysu.edu.cn.
  • Supported by:
    This study was supported by the National Key R&D Project of China, No. 2020YFA0112701 (to YZ); the National Natural Science Foundation of China, Nos. 82171057 (to YZ), 81870657 (to YL); Science and Technology Program of Guangzhou of China, No. 202206080005 (to YZ); and the Natural Science Foundation of Guangdong Province of China, No. 2022A1515012168 (to YL).

PDF

182

Abstract: Vision depends on accurate signal conduction from the retina to the brain through the optic nerve, an important part of the central nervous system that consists of bundles of axons originating from retinal ganglion cells. The mammalian optic nerve, an important part of the central nervous system, cannot regenerate once it is injured, leading to permanent vision loss. To date, there is no clinical treatment that can regenerate the optic nerve and restore vision. Our previous study found that the mobile zinc (Zn2+) level increased rapidly after optic nerve injury in the retina, specifically in the vesicles of the inner plexiform layer. Furthermore, chelating Zn2+ significantly promoted axonal regeneration with a long-term effect. In this study, we conditionally knocked out zinc transporter 3 (ZnT3) in amacrine cells or retinal ganglion cells to construct two transgenic mouse lines (VGATCreZnT3fl/fl and VGLUT2CreZnT3fl/fl, respectively). We obtained direct evidence that the rapidly increased mobile Zn2+ in response to injury was from amacrine cells. We also found that selective deletion of ZnT3 in amacrine cells promoted retinal ganglion cell survival and axonal regeneration after optic nerve crush injury, improved retinal ganglion cell function, and promoted vision recovery. Sequencing analysis of reginal ganglion cells revealed that inhibiting the release of presynaptic Zn2+ affected the transcription of key genes related to the survival of retinal ganglion cells in postsynaptic neurons, regulated the synaptic connection between amacrine cells and retinal ganglion cells, and affected the fate of retinal ganglion cells. These results suggest that amacrine cells release Zn2+ to trigger transcriptomic changes related to neuronal growth and survival in reginal ganglion cells, thereby influencing the synaptic plasticity of retinal networks. These results make the theory of zinc-dependent retinal ganglion cell death more accurate and complete and provide new insights into the complex interactions between retinal cell networks.

Key words: axonal regeneration, conditional knockout, neurotransmitter, optic nerve injury, presynaptic neuron, retinal network, synaptic connection, synaptic vesicles, visual acuity, zinc transporter 3