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Hari Ramakrishnan, Sandeep Kumar, Suresh Viswanathan, Abram Akopian, Stewart A Bloomfield; Blockade of neuronal gap junctions preserves the structural and functional integrity of the retina and optic nerve in a mouse model of glaucoma. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2571.
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© ARVO (1962-2015); The Authors (2016-present)
We showed at ARVO last year that the gap junction (GJ)-mediated bystander effect plays a crucial role in the progressive loss of inner retinal neurons in glaucoma. Here we examined whether blockade of neuronal GJs can preserve the normal structure and function of the glaucomatous retina and optic nerve of the mouse.
Experimental glaucoma was induced in adult C57BL/6 (WT) and connexin (Cx) knockout (KO) mice by raising IOP with intracameral injections of polystyrene microbeads. ERG and VEPs were recorded to assess retinal and cortical function. Retinal neurons and optic nerve axons were immunolabeled with specific markers to determine cell/axonal loss. Statistical significance was determined using Student’s t-test.
Eight weeks after initial bead injection, the amplitudes of the positive scotopic threshold response (STR) (-4 log sc.cd.s/m2 stimulus) and summed oscillatory potential (OP) (-0.4 log sc.cd.s/m2 stimulus) were attenuated by 51% (p<0.005) and 47% (p<0.005), respectively, relative to control values. The amplitude of VEPs recorded in these mice was reduced by 71% (p<0.05). Cell counts of retinal ganglion cells and selective subpopulations of amacrine cells were reduced by 34% (p<0.001) and 17-50% (p<0.001), respectively, at 8 weeks post initial bead injection. Optic nerve cross-sections obtained from glaucomatous eyes showed a 45% (p<0.001) reduction in axonal density as compared to control values. Glaucoma was induced in retinas in which GJs were blocked by intravitreal injections of meclofenamic acid or genetically ablated in Cx36 KO mice. We found that blockade or ablation of GJs offered substantial protection. This was indicated by amplitude measures for STRs, OPs, and VEPs as well as counts of retinal neurons and optic nerve axons in glaucomatous eyes that were not statistically different from those measured in control animals.
We found that induction of experimental glaucoma in mice produced electrophysiological changes that mirrored the loss of retinal neurons and axons in the optic nerve. Moreover, our data show that blockade or ablation of GJs preserves both the normal structure and function of the retina and optic nerve. Our results indicate that neuronal GJs form novel therapeutic targets for treatments directed at reducing the progressive loss of neurons and axons in glaucoma.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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