中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (on line): 1-8.

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Selective deletion of zinc transporter 3 by amacrine cells can promote retinal ganglion cell survival and optic nerve regeneration

  

  • 出版日期:2023-01-01 发布日期:2023-02-25

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:2023-01-01 Published:2023-02-25
  • 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, China, No. 202206080005 (to YZ); and the Natural Science Foundation of Guangdong Province of China, No. 2022A1515012168 (to YL).

摘要: https://orcid.org/0000-0002-3483-7189 (Yiqing Li); https://orcid.org/0000-0003-3247-7199 (Yehong Zhuo)

Abstract: Vision depends on accurate signal conduction from the retina to the brain through the optic nerve, which consists of bundles of axons originating from retinal ganglion cells. As an important part of the central nervous system, the mammalian optic nerve 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 mobile zinc (Zn2+) level increased rapidly after optic nerve injury in the retina, specifically in the vesicles of the inner plexiform layer. 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 and retinal ganglion cells to construct two kinds of transgenic mice (VGATCreZnT3fl/fl and VGLUT2CreZnT3fl/fl) and obtained the direct evidence that the rapidly increased free ZnT3 were 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 anacrine cells and retinal ganglion cells, and thus affect the fate of retinal ganglion cells. These results suggest that anacrine cells releasing Zn2+ triggers transcriptomic changes related to neuronal growth and survival in reginal ganglion cells and influences the synaptic plasticity of retinal networks. These results make the theory of zinc-dependent retinal ganglion cell death more accurate and complete, and also provide new insights into the complex interaction 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 transporter3