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

doi:10.4103/1673-5374.373660

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

Neural Regen Res. 2023 Dec;18(12):2773-2780. doi: 10.4103/1673-5374.373660.

Authors

Zhe Liu¹, Jingfei Xue¹, Canying Liu¹, Jiahui Tang¹, Siting Wu¹, Jicheng Lin¹, Jiaxu Han¹, Qi Zhang¹, Caiqing Wu¹, Haishun Huang¹, Ling Zhao¹, Yehong Zhuo¹, Yiqing Li¹

Affiliation

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, Guangzhou.

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 (VGAT^CreZnT3^fl/fl and VGLUT2^CreZnT3^fl/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.

Keywords: axonal regeneration; conditional knockout; neurotransmitter; optic nerve injury; presynaptic neuron; retinal network; synaptic connection; synaptic vesicles; visual acuity; zinc transporter 3.