Manipulating Glia to Protect Retinal Ganglion Cells in Glaucoma

Abstract

Increasing evidence supports both direct and indirect roles for retinal glia in the pathogenesis of glaucoma. To complicate these roles is the realization that glial activity can be both beneficial and detrimental to the survival of retinal ganglion cells (RGCs) and their axons. The contribution of glia to glaucoma pathogenesis also varies by compartment; glia in retina react differently to disease-induced stressors than glia in the optic nerve head or in the optic nerve. We will describe the evidence to date for the various roles of glia in each of these compartments. From this foundation, we have explored two hypotheses: whether manipulating gliosis can protect RGCs or their axons; and whether manipulating the antioxidant supportive role of retinal glia could prevent RGC degeneration and preserve vision. Encouragingly, we have observed that retinal gliosis can be altered to positive effect for RGCs. Improving glial support of RGCs has also increased RGC and optic nerve axon survival. Glia greatly outnumber neurons in the CNS, but due to their reputation as secondary support cells, their study has lagged that of neurons. Within the retina, there are three types of glia: Astrocytes and Muller glia (the macroglia), and microglia. The Muller glia form the structural scaffolding of the retina, with endfeet that comprise both the inner and outer limiting membranes. The astrocytes reside among the retinal ganglion cells and their axons, while the microglia exist in non-overlapping tiled arrangements throughout the neuronal and synaptic layers of the inner retina (Bosco et al., 2011). Astrocytes and Muller glia provide homeostatic support to retinal neurons, including neurotransmitter and ion buffering, and anti-oxidant, nutrient and growth factor provision. Microglia, the resident immune cells, survey the retinal environment and respond to changes or threats. Muller glia, a macroglia subtype specific to the retina, serve all of the functions of parenchymal astrocytes, but with additional unique qualities such as transdifferentiation after specific kinds of injury (Bringmann & Reichenbach, 2001). Glia have garnered attention in the visual system through their emergence as fascinating arbiters of health and disease. Glia respond quickly to even the slightest homeostatic alterations, including pressure, electrical activity, infection, degeneration, and pH changes. Astrocytes and Muller glia undergo gliosis in response to many of these stimuli, a cellular hypertrophy that includes, but is not limited to, upregulating the intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin. GFAP expression is always apparent in astrocytes, but Muller glia only express this intermediate filament in times of