Retinal glial activation in the contralateral eyes in a mouse model of unilateral laser‐induced glaucoma
Authors: Salobrar‐Garcia Elena 
Published: December 2022

AbstractGlaucoma is a neurodegenerative chronic pathology, characterized by the loss of retinal ganglion cells (RGC), which leads to an irreversible vision field loss. The glaucomatous optic neuropathy is usually a bilateral disease, though asymmetric in time: this means that the damage initially present in one of the eyes, eventually also appears with a time delay in the contralateral eye. Notably, recent experimental models of unilateral ocular hypertension (OHT) have shown that the fellow normotensive contralateral eyes to hypertensive eyes exhibit changes in glial cells with little or no damage to RGCs.It has been reported that although increased intraocular pressure (IOP) may be the main trigger for this pathology, other pathogenic mechanisms such as neuroinflammation are involved in the RGCs death. Microglial cells constitute the population of immune resident cells, and they play an important role in the physiology and survival of RGC.One of the most widely used experimental models of glaucoma is the unilateral laser‐induced OHT model. In these animals, OHT induces an alteration of retrograde axonal transport in RGCs and a subsequent degeneration of these cells. In this model, at different time‐points after OHT induction (1, 3, 5, 8 and 15 days), the microglia exhibited different signs of activation, such as proliferation and migration to areas of damage, retraction, reorientation, and hyper‐ramification of their processes, soma thickening and the appearance of amoeboid‐ and rod‐like microglia with macrophagic capacity, related to RGC degeneration. All these changes were most intense at 3–5 days after OHT induction in the OHT eye. This was confirmed by the decreased expression of the purinergic receptor P2RY12, which would indicate higher microglial activation.In this model, at all time‐points after OHT induction, the activation of the macroglia (astrocytes and Müller cells) has also been demonstrated, showing morphological changes, as well as an overexpression of glial fibrillary acidic protein (GFAP).In this laser‐induced OHT model, an MHC‐II overexpression was observed in the microglia, astrocytes, and Müller cells, allowing these cells to induce a T‐cell mediated immune response.Significant changes in the expression of proinflammatory (IL‐1β, IL‐6, INF‐γ, IL‐17), anti‐inflammatory (IL‐4, IL‐10) and myokines (Fractalkine, BDNF, VEGF) cytokines were also observed.The same changes in glial cells (microglia, astrocytes and Müller cells) as well as in the expression of different cytokines and myokines were observed in the contralateral normotensive eyes at the different time points after OHT induction although with a lower intensity.Based on the alterations found in the contralateral eye, it can be concluded that this eye should not be used as a control eye in experimental models of unilateral glaucoma. Changes in contralateral normotensive eyes could exhibit the initial events of glaucomatous neurodegeneration, probably mediated by inflammatory mechanisms. Therefore, studies focusing on contralateral eyes could improve our understanding of glaucomatous pathophysiology. The study of the contralateral eye appears to have the potential for discovering points of intervention to which future neuroprotective therapeutics can be directed.