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Mingui Zhang, Shan Gao, Tatjana C Jakobs; Optic nerve head astrocytes sense injury to ganglion cell axons at a distance. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3735. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
In the optic nerve head (ONH), the unmyelinated axons of retinal ganglion cells are in direct contact with astrocytes. Injury to the optic nerve - be it traumatic or glaucomatous - leads to reactive changes in the cell morphology and gene expression pattern. Previous experiments have shown that astrocytes can react very quickly to an increase in intraocular pressure (IOP) and that optic nerve astrocytes express a variety of mechanosensitive channels. It is therefore plausible that astrocytes directly sense elevated IOP. However, astrocytes may also become reactive in response to biochemical signals released from injured axons. The purpose of our present study was to find out whether astrocytes in the ONH can sense an injury to ganglion cell axons over a distance of several millimeters, which would indicate that an axonal “distress signal” is involved.
Retro-orbital optic nerve crush inevitably injures not only the ganglion cell axons but also the surrounding astrocytes. Therefore, we selectively injured ganglion cell axons by stereotaxic transection of the intracranial portion of the optic nerve while leaving ONH astrocytes completely intact. One and three days later, RNA was isolated from the ONH and the gene expression profile was characterized by Affymetrix microarray screening. Differential expression was defined as an up- or down-regulation of at 1.5-fold or more compared to an uninjured control. Results were validated by quantitative PCR, immunohistochemistry, and electron microscopy (EM).
One and three days after transection of the intracranial optic nerve, 132 and 1403 genes were differentially expressed in the ONH, respectively. These included several genes typically associated with astrocyte reactivity in other models of optic nerve injury and glaucoma (e.g. lipocalin-2, osteopontin, Serpin3A1, selectin-P). Pathway analysis predicted that – similar to direct nerve crush and early stages of glaucoma – CSF2, IL1, and TNF pathways are up-regulated. One day after transection, the ONHs appeared morphologically normal. After 3 days, EM revealed significant changes in the size of axonal mitochondria, axonal swelling, and the appearance of individual macrophages/activated microglial cells in the axon bundles of the nerve.
Astrocytes in the ONH react to an axonal injury several millimeters away from the lesion site.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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