Neurotoxic Reactive Astrocytes Drive Neuronal Death after Retinal Injury

Kevin A Guttenplan,Benjamin K Stafford,Rana N El-Danaf,Drew I Adler,Alexandra E Münch,Maya K Weigel,Andrew D Huberman,Shane A Liddelow

doi:10.1016/j.celrep.2020.107776

Abstract

Glaucoma is a neurodegenerative disease that features the death of retinal ganglion cells (RGCs) in the retina, often as a result of prolonged increases in intraocular pressure. We show that preventing the formation of neuroinflammatory reactive astrocytes prevents the death of RGCs normally seen in a mouse model of glaucoma. Furthermore, we show that these spared RGCs are electrophysiologically functional and thus still have potential value for the function and regeneration of the retina. Finally, we demonstrate that the death of RGCs depends on a combination of both an injury to the neurons and the presence of reactive astrocytes, suggesting a model that may explain why reactive astrocytes are toxic only in some circumstances. Altogether, these findings highlight reactive astrocytes as drivers of RGC death in a chronic neurodegenerative disease of the eye.

Highlights

Glaucoma is a neurodegenerative disease marked by axonal damage of retinal ganglion cells (RGCs) that results in RGC death and vision loss
As in many neurodegenerative diseases, dysfunction in mouse models of glaucoma is coupled with a response of the surrounding glial cells in the retina and optic nerve known as gliosis, usually measured by increases in the protein and transcript of glial fibrillary acidic protein (GFAP) (Inman and Horner, 2007; Sun et al, 2017; Wang et al, 2017)
RGCs Die after Acute Axonal Injury We first investigated the timing of RGC death following acute axotomy using the retro-orbital optic nerve crush (ONC) model (Frank and Wolburg, 1996; Tang et al, 2011)

Summary

Introduction

Glaucoma is a neurodegenerative disease marked by axonal damage of retinal ganglion cells (RGCs) that results in RGC death and vision loss. As in many neurodegenerative diseases, dysfunction in mouse models of glaucoma is coupled with a response of the surrounding glial cells in the retina and optic nerve known as gliosis, usually measured by increases in the protein and transcript of glial fibrillary acidic protein (GFAP) (Inman and Horner, 2007; Sun et al, 2017; Wang et al, 2017). This response increases with disease progression (Bosco et al, 2016), suggesting a mechanistic link between gliosis and degenerative pathology

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Discussion

Conclusion