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Review
. 2022 Nov 17:16:995369.
doi: 10.3389/fnana.2022.995369. eCollection 2022.

The heterogeneity of astrocytes in glaucoma

Yunjing Tang  1   2 , Yongjiang Chen  3 , Danian Chen  1   2
Affiliations
Review

The heterogeneity of astrocytes in glaucoma

Yunjing Tang et al. Front Neuroanat. .

Abstract

Glaucoma is a leading cause of blindness with progressive degeneration of retinal ganglion cells. Aging and increased intraocular pressure (IOP) are major risk factors. Lowering IOP does not always stop the disease progression. Alternative ways of protecting the optic nerve are intensively studied in glaucoma. Astrocytes are macroglia residing in the retina, optic nerve head (ONH), and visual brain, which keep neuronal homeostasis, regulate neuronal activities and are part of the immune responses to the retina and brain insults. In this brief review, we discuss the activation and heterogeneity of astrocytes in the retina, optic nerve head, and visual brain of glaucoma patients and animal models. We also discuss some recent transgenic and gene knockout studies using glaucoma mouse models to clarify the role of astrocytes in the pathogenesis of glaucoma. Astrocytes are heterogeneous and play crucial roles in the pathogenesis of glaucoma, especially in the process of neuroinflammation and mitochondrial dysfunction. In astrocytes, overexpression of Stat3 or knockdown of IκKβ/p65, caspase-8, and mitochondrial uncoupling proteins (Ucp2) can reduce ganglion cell loss in glaucoma mouse models. Based on these studies, therapeutic strategies targeting the heterogeneity of reactive astrocytes by enhancing their beneficial reactivity or suppressing their detrimental reactivity are alternative options for glaucoma treatment in the future.

Keywords: astrocytes; glaucoma; heterogeneity; inflammation; intraocular pressure; mitochondrial dysfunction; optic nerve head; retinal ganglion cells.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Astrocytes in the visual pathway may be related to the pathogenesis of glaucoma. (A) The schematic diagram showing the visual pathway, including retina, optic nerve, optic chiasma, LGN, SCs, and visual cortex. (B) Retinal astrocytes mainly reside in the nerve fiber layer (NFL) and orient in a monolayer surrounding RGC axons and blood vessels. (C) Optic nerve head (ONH) astrocyte processes are oriented perpendicularly to RGC axons, separating them into bundles. The two dash lines label the position of LC (human) or glia lamina (rat or mouse). (D) Visual brain astrocytes in LGN, SCs, and visual cortex, have two types including protoplasmic astrocytes of gray matter and fibrous astrocytes of white matter. LGN, lateral geniculate nucleus; LC, lamina cribrosa; NFL, the nerve fiber layer; ONH, optic nerve head; RGC, retinal ganglion cells; SCs, superior colliculi.
Figure 2
Figure 2
Main physiological functions of astrocytes and features of reactive astrocytes in glaucoma.
Figure 3
Figure 3
Retinal astrocyte activation in glaucoma is heterogeneous and is stage-dependent and spatially dependent. In the early stage of OHT/glaucoma, or the peripheral retina of late-stage glaucoma, cell density and GFAP expression of astrocytes are reduced. Astrocyte activation seems only to occur in some retinal areas of later-stage glaucoma, especially areas close to ONH. OHT, ocular hypertension; ONH, optic nerve.
Figure 4
Figure 4
ONH astrocyte activation in glaucoma is heterogeneous and stage dependent. (A) Transient OHT induces reversible morphological remodeling of ONH astrocytes. (B) In the early stage of OHT, morphological remodeling persists, Cx43 and GFAP expression of ONH astrocytes are reduced. Cell division and cell number increased. (C) In DBA/2J mouse models of glaucoma, γ-synuclein-dependent phagocytosis increased, astrocyte spout longitudinal and GFAP− processes. At late-stage, astrocytes can form scars. (D) In late stage of glaucoma patients, ONH astrocytes have morphological remodeling and increased expression of CX43 and GFAP. The two dash lines label the position of LC (human) or glia lamina (rat or mouse). LC, lamina cribrosa; OHT, ocular hypertension.
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