Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension

Abstract

Purpose : Glaucoma is characterized by progressive loss of retinal ganglion cells (RGCs), resulting in irreversible visual deficits. Cyclic AMP (cAMP) is a universal second messenger that regulates many pathophysiological processes. Yet the role of cAMP and its downstream mediators in neurodegeneration in glaucoma are largely unknown. Exchange protein activated by cAMP (Epac) is a newly identified mediator of cAMP. Here, we assessed the role of cAMP/Epac1 pathway in RGC injury in two mouse models of ocular hypertension.

Methods : Mouse model of retinal ischemia-reperfusion (IR) was induced by increasing the intraocular pressure (IOP) to 110 mm Hg to block retinal blood flow for 45 minutes followed by restoring normal IOP to allow reperfusion. Microbead-induced glaucoma model was induced by injecting polystyrene microbeads into anterior chamber to inhibit the drainage of aqueous humor, resulting in a moderate but sustained increase in IOP similar to that in chronic glaucoma.

Results : The level of cAMP and the activity and expression of Epac1 were increased in retinas of two mouse models. Genetic depletion of Epac1 significantly attenuated ocular hypertension-induced detrimental effects in the retina, including vascular inflammation, neuronal apoptosis and necroptosis, thinning of ganglion cell complex layer, RGC loss and retinal neuronal dysfunction. With bone marrow transplantation and various Epac1 conditional knockout mice, we further demonstrated that Epac1 in retinal neuronal cells (especially RGCs) was responsible for their death. Consistently, pharmacologic inhibition of Epac activity prevented RGC loss. Moreover, in vitro study on primary RGCs showed that Epac1 activation was sufficient to induce RGC death, which was mechanistically mediated by CaMKII activation.

Conclusions : These findings indicate neuronal Epac1 plays a critical role in retinal neurodegeneration and suggest that Epac1 could be considered a target for neuroprotection in glaucoma.

This is a 2020 ARVO Annual Meeting abstract.