Abstract
Glaucoma is a progressive neurodegenerative disease of retinal ganglion cells (RGCs) associated with characteristic axon degeneration in the optic nerve. Excitotoxic damage due to increased Ca2+ influx, possibly through NMDA-type glutamate receptors, has been proposed to be a cause of RGC dysfunction and death in glaucoma. Recent work has found that expression of another potentially critical receptor, the Ca2+-permeable AMPA receptor (CP-AMPAR), is elevated during various pathological conditions (including ALS and ischemia), resulting in increased neuronal death. Here we test the hypothesis that CP-AMPARs contribute to RGC death due to elevated Ca2+ influx in glaucoma. AMPA receptors are impermeable to Ca2+ if the tetrameric receptor contains a GluA2 subunit that has undergone Q/R RNA editing at a site in the pore region. The activity of ADAR2, the enzyme responsible for this RNA editing, generally ensures that the vast majority of GluA2 proteins are edited. Here, we demonstrate that ADAR2 levels decrease in a mouse model of glaucoma in which IOP is chronically elevated. Furthermore, using an in vitro model of RGCs, we find that knockdown of ADAR2 using siRNA increased the accumulation of Co2+ in response to glutamate, and decreased the rectification index of AMPA currents detected electrophysiologically, indicating an increased Ca2+ permeability through AMPARs. The RGCs in primary culture also exhibited increased excitotoxic cell death following knock down of ADAR2. Furthermore, cell death was reversed by NASPM, a specific blocker for CP-AMPARs. Together, our data suggest that chronically elevated IOP in adult mice reduces expression of the ADAR2 enzyme, and the loss of ADAR2 editing and subsequent disruption of GluA2 RNA editing might potentially play a role in promoting RGC neuronal death as observed in glaucoma.
Highlights
Glaucoma is the second leading cause of blindness overall, and the leading cause of blindness in the African American community [1]
While it is understood that all of these factors contribute to the loss of retinal ganglion cells (RGCs) in glaucoma, this study focused on glutamate excitotoxicity as an underlying cause of RGC death
The scarcity of terminal deoxytransferasemediated dUTP nick end-labeling (TUNEL) positive cells in GCL layer of model mice at 6 weeks suggested that RGC death was chronically induced in the microbeads-injected glaucoma model, which is consistent with the natural history of glaucoma
Summary
Glaucoma is the second leading cause of blindness overall, and the leading cause of blindness in the African American community [1]. Years of intensive research on the part of both clinical and basic research scientists have led to the understanding that a number of different underlying mechanisms contribute to this disease. These include: neurotropic factor deprivation [4,5], axonal transport failure [6,7], activation of intrinsic and extrinsic apoptotic signals [8,9], oxidative stress [10], hypoperfusion/ischemia of the anterior optic nerve [11], glial cell activation [12,13] and glutamate excitotoxicity [14,15]. While it is understood that all of these factors contribute to the loss of RGCs in glaucoma, this study focused on glutamate excitotoxicity as an underlying cause of RGC death
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