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Editors Selection IGR 12-4

Basic Science: Neuroprotection - role of astrocyte reactivity

Comment by Peng Tee Khaw on:

72868 Optic nerve astrocyte reactivity protects function in experimental glaucoma and other nerve injuries, Sun D; Moore S; Jakobs TC, Journal of Experimental Medicine, 2017; 214: 1411-1430

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Although there have been some criticisms of the use of the mouse and rat model for raised intraocular pressure in the model of glaucoma, in part because the mouse and rat lack the lamina cribosa found in the primate optic nerve. Nonetheless these mod-els have proved very useful. In particular, raising the pressure in these eyes appears to cause a similar cycle of axonal and subsequent ganglion cell body death seen in primary glaucoma. Given that there are two major cell types in the rat and mouse optic nerve head i.e. the astrocytes which form a living cellular lamina and the ganglion cell axons which run through the optic canal intimately in contact with the astrocytes, this suggests that the disruption of the astrocytic axonal relationship is a fundamental part of the diseases we call glaucoma.

In this paper the authors have concentrated on a signal transducer and activator of transcription 3 (STAT3) which is a cellular transcription factor. The molecule has various functions. Within the nervous system it is a regulator of astrocyte reactivity and glial scar formation in the brain and spinal cord. Astrocytes in the nervous system all express STAT3 and activation of this molecule increases after events such as trauma and inflammation and also in elevated intraocular pressure in the rat. In the brain and spinal cord the expression of STAT3 attenuates the amount of damage after injury.

Using a knock-out model, the authors investigated the changes in STAT3 expression was associated with cellular phenotype and damage to the axon in a model of raised pressure in the mouse created by microbead injection.

pSTAT3 was upregulated in reactive astrocytes within the glial lamina. Retinal astrocytes did not show upregulation of pSTAT3.

Interestingly, there was some activation of STAT3 in some of the retinal Müller cells that have been postulated to carry out similar support functions to the retinal nerve fibre layer in the retina. With injury due to raised pressure, hypertrophy and reaction of the astrocytes are noted and the reactive astrocytes also expressed glial fibrillary acidic protein. The damage to astrocytes resulted in the expulsion of various biomarkers of activation in the glial lamina of the mice, while a knockout of STAT3 did not show a similar phenotypic reaction.

Lack of reactive astrocytes was associated with significantly greater ganglion cell loss. In addition, using the positive scotopic threshold response (or pSTR) the mice with the STAT3 knockout showed 20% to 30% greater reduction in the amplitude of the pSTR reflecting ganglion cell dysfunction.

What the study shows, at least in this model, is that STAT3 appears to be an important component of the reaction of the astrocytes to raise pressure. The lack of STAT3 is associated with greater damage to the axons and ganglion cells. This also continues to confirm the intimate relationship between the astrocyte and the axon in that the reactivity or otherwise at the astrocyte is potentially extremely important in modifying damage to the axon and subsequently the ganglion cell body.

The intimate relationship between the astrocyte and axon is clearly going to be one of the keys to fully understanding and treating this enigmatic group of diseases known as glaucoma

There is also commentary about the fact that a single transient elevation of pressure to about 30mmHg for just a few hours can cause very long term damage, confirming the findings of other authors. Again raising the discussion about the primary mechanisms of long term continued damage to the axons appear to be related to long term cellular changes initiated by barotrauma in the form of raised intraocular pressure. This also suggests that the intimate relation between the astrocyte and axon is clearly going to be one of the keys to fully understanding and treating this enigmatic group of diseases known as glaucoma.

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