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Kimberly A Wong, Sheri Peterson, Larry Benowitz; Zinc and microglia regulate retinal ganglion cell survival and axon regeneration after optic nerve injury. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5176.
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© ARVO (1962-2015); The Authors (2016-present)
Optic nerve injury leads to irreversible blindness due to the inability of retinal ganglion cells (RGCs) to regenerate their axons and the progressive loss of these cells. Our limited understanding of the signals that trigger RGC death after injury or disease has prevented the development of curative therapies. Two phenomena common to many neurodegenerative disorders of the central nervous system are activation of inflammation and elevation of mobile zinc (Zn2+). Our objective was to investigate whether Zn2+ elevation has a role in microglial activation after optic nerve crush (ONC) injury and to identify the consequences of microglial activation on RGC survival and optic nerve regeneration.
For these studies we utilized an optic nerve crush (ONC) injury model in 129S1 mice. Microglia were visualized and quantified by immunostaining for Iba1 (cell morphology) and CD68 (lysosomal marker). Microglial activation was scored by assessment of cell morphology and phagocytic activity (Ryuta scale, developed by the Beth Stevens lab). Zn2+-selenite autometallography was used to visualize Zn2+ in retinal sections. To investigate the effect of microglia on the fate of RGCs, we ablated microglia by systemic treatment with the CSF-1R inhibitor PLX5662 delivered via chow for 14 days.
We previously observed that Zn2+ is elevated in amacrine cell terminals within 6 hr after ONC, peaking at 1-day post injury (dpi). Zn2+ is then exocytosed and accumulates in RGCs between 2-3 dpi. Intraocular treatment with a Zn2+ chelator (TPEN or ZX1) at the time of ONC represses Zn2+ elevation and increases RGC survival and axon regeneration. Here, we found that microglial proliferation and activation increases by 3 dpi and that Zn2+ chelation partially represses microglia activation but not proliferation. Treatment with PLX5622 led to a 96% decrease in microglial density in the retina, and contrary to a previous report, loss of microglia enhanced RGC axon regeneration after injury.
Our results indicate that Zn2+ chelation partially prevents microglial activation after ONC, and that ablation of microglia increases RGC regeneration. These results suggest that microglia regulate the ability of RGCs to regenerate their axons.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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