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William M McLaughlin, Michael G Dubner, Cathryn Formichella, Rebecca M Sappington; Ccl-5 Deficiency Impedes Retinal Ganglion Cell Axonopathy in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2956.
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© ARVO (1962-2015); The Authors (2016-present)
Ccl-5, a beta-chemokine, is constitutively expressed in retina and is associated with inflammatory and neuroprotective responses in several neurodegenerative disorders. We examined whether Ccl-5 deficiency alters retinal ganglion cell (RGC) degeneration in glaucoma.
We induced unilateral glaucoma for 6 weeks in age-matched, 8 month old C57Bl/6 (WT) and ccl5-/- mice, using the Microbead Occlusion Model. Intraocular pressure (IOP) was monitored by tonometry. Visual function was assessed prior to and six weeks after model induction, using electroretinogram. For axon transport analysis, mice received bilateral intravitreal injection of the neural tracer cholera toxin beta subunit (CTB) 3 days prior to sacrifice. RGC connectivity was assessed by quantification of CTB anterograde transport to the superior colliculus(SC) and immunohistochemical examination of RGC pre-synaptic inputs in retina of whole eye sections. Structural degeneration of RGCs was assessed retina and optic nerve. Paired and unpaired T-tests were utilized for statistical analysis with p>0.05 indicating statistical significance.
Baseline IOP and experimental IOP did not differ between WT and ccl5-/- mice (p>0.05). For both genotypes, microbead injection elevated IOP by 22-25% throughout the 6 week period, compared to saline injection (p < 0.01 for both). In WT mice, elevated IOP resulted in a 28-36% decrease in Brn3a+ RGCs in the retina and RGC axons in the optic nerve (p<0.05), compared to saline-injected controls. These pressure-induced decreases were not observed in ccl5-/- mice, compared to saline-injected controls (p>0.05). The number of degenerating axon profiles increased by nearly 10-fold in optic nerve from WT mice versus only 3-fold in ccl5-/- mice (p<0.05). Anterograde transport of CTB to the SC decreased by almost 40% in WT mice (p<0.01), but not in ccl5-/- mice. Retina from microbead-injected WT mice exhibited reorganization of beta-tubulin+ processes in the inner plexiform layer. This reorganization was significantly less noticable in ccl5-/- mice than WT. IOP-dependent pathology noted in WT mice was accompanied by decreases in amplitudes of b-wave and oscillatory potentials, particularly for the combined cone and rod response (p<0.05). This decrease was not observed in ccl5-/- mice.
Our data suggests that Ccl5 deficiency improves structural and functional outcomes for RGCs in a mouse model of inducible glaucoma.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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