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Silvia Pasini, Michael Risner, Melissa Cooper, Wendi S Lambert, David J Calkins; Relationship between somato-dendritic and axonal degeneration in a mouse model of ocular hypertension.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3714.
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© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is the most prevalent optic neuropathy and a leading cause of irreversible blindness. The disease affects retinal ganglion cells (RGCs) through sensitivity to intraocular pressure (IOP), which ultimately causes Bax-dependent apoptosis. To develop effective therapeutic strategies requires dissection of how different neuronal compartments respond during disease progression. Early prominent features of glaucoma include dendritic pruning and axonal dysfunction. Here we assess if deletion of Bax, which protects RGC bodies, also influences RGC dendritic pruning and axonal degradation caused by increased IOP.
We increased IOP unilaterally by microbead occlusion of the anterior chamber in age-matched Bax knock-out (KO) and wild type (WT) mice. The contralateral eye received an equivalent volume saline injection, following our published protocols. We used optokinetic reflex to track visual acuity over time and compared these results to levels of intact anterograde transport from the retina to brain to assess RGC axon function and to dendritic complexity, field area and total dendritic length for different RGC types identified morphologically.
Microbead-induced elevation of IOP led to a significant deficit in visual acuity starting one week post-injection in WT mice and two weeks post-injection in Bax KO mice compared to the respective saline controls (1wk: WT p=0.012, KO p=0.092; 2wk: WT p=2x10-7, KO p=0.0008). Also, Bax deficiency reduced the deficit in the anterograde transport of cholera toxin b to the superior colliculus caused by microbead-induced elevation in IOP compared to WT (50% deficit in WT microbead group and 35% deficit in Bax KO microbead group compared to the respective saline groups, WT p=0.0013, KO p=0.0011). Finally, morphological analysis of different classes of RGCs revealed that Bax deficiency prevented dendritic pruning detected in WT mice after four weeks of increased IOP. In particular, this protective effect occurred only in the αON and in the ON dendrites of ON-OFF RGCs, while αOFF-T and OFF dendrites of ON-OFF RGCs still exhibited dendritic pruning.
Our results show that compared to WT, Bax deficiency reduces axon dysfunction, visual acuity loss, and pruning of ON RGC dendrites. These data suggest a more complex role for Bax in glaucoma pathogenesis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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