Abstract
Purpose:
Excitotoxic damage due to elevated intracellular Ca2+ levels has been proposed to mediate RGC dysfunction and death in glaucoma. We sought to explore the function and potential role of ADAR2 and Ca2+-permeable AMPARs in experimentally induced glaucoma.
Methods:
Glaucoma model was set up by intracameral injection of latex microbeads, which elevate intraocular pressure (IOP) by blocking drainage through the trabecular meshwork. Immunohistochemical labeling of ADAR2 was examined in mouse retina using antibodies specific for ADAR2. mRNA expression levels of ADAR2 were measured in glaucoma model. For functional evaluation, primary RGCs were cultured and ADAR2 expression was knocked down using siRNA. TUNEL, Co2+ and Ca2+ imaging was used to evaluate increased susceptibility of RGCs to excitotoxic cell death.
Results:
ADAR2 was specifically expressed in RGCs. We found a 50% decrease in ADAR2 expression in the retina in response to increased IOP in the intracameral injection/TM obstruction glaucoma model at 6 weeks. In primarily cultured RGCs, loss of ADAR2 expression using siRNA increased the susceptibility of RGCs to AMPA induced excitotoxicity. Furthermore, when we knocked down ADAR2, the expression of Ca2+ permeable AMPARs was increased.
Conclusions:
We initially investigated the function of reduced ADAR2 levels on RGCs function and viability. This work suggests that ADAR2 may play a role in the pathogenesis of glaucoma and identifies a novel target for the therapeutic intervention in glaucoma.
Keywords: 439 calcium •
518 excitatory neurotransmitters •
531 ganglion cells