The Role of Astroglial Connexin43 in Experimental Glaucoma.

Abstract

Glaucoma is an irreversible blinding disease due to progressive loss of retinal ganglion cells (RGCs) and their axons. Astrocytes are glial cells that reside in the retinal nerve fiber layer (RNFL) closely to RGC bodies and unsheathe axons in the optic nerve head. Astrocytes play an important role in the pathogenesis of glaucoma. A unique feature of astrocytes is that they are extensively coupled by gap junctions (GJ) composed of connexin 43 (Cx43). In addition, unopposed Cx43 hemichannels can open in pathological conditions and release signaling molecules (e.g., ATP and excess glutamate). The role of astrocytic Cx43 GJ and hemichannels in glaucoma is unclear. Here we studied the effect of Cx43 deletion in astrocytes in normal conditions and in glaucomatous injuries. Results show that deletion of Cx43 does not affect normal retinal function, potentially due to direct coupling of astrocytes to Müller glia. Microbead-induced elevation of IOP increased Cx43 expression and GJ coupling in astrocytes. Importantly, astrocyte-specific deletion of Cx43 markedly reduced RGC death and preserved visual function in glaucomatous mice. Absence of Cx43 in astrocytes also reduced microglial activation in glaucoma but did not affect astrocyte reactivity. Additionally, intravitreal injections of Gap19 peptide, a selective Cx43 hemichannel blocker, markedly increased RGC survival and improved RGC function, indicating a contribution of activated Cx43 hemichannels in glaucoma progression. Therefore, targeting Cx43 hemichannels might be a new therapeutic approach to the treatment of glaucoma.