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D. J. Calkins, D. Inman, P. Horner, S. Crish; Progression of Deficits in Anterograde Active Axonal Transport in the Retina of the DBA/2J Mouse Model of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4317.
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Compromised axonal transport is a known contributor to the pathogenesis of glaucomatous neurodegeneration. Our studies indicate that distal deficits in transport (optic tract to brain) are relevant to retinal ganglion cell injury in the DBA/2J mouse model of pigmentary glaucoma. To better understand the progression of transport deficits in this model, we compared active retinal uptake and transport of the neuronal tracer cholera toxin β-subunit (CTB) to cell-specific markers and indicators of axonal dystrophies.
We injected intravitreally 1ul of 1% fluorophore-conjugated CTB in 3-12 mo DBA/2J animals. After a 48 hour recovery, animals were perfused and the brain and retinas harvested. Transport to the superior colliculus (SC) was analyzed in coronal sections, while retinas were flat-mounted and immune-labeled for the axonal cytoskeleton proteins phosphorylated heavy-chain neurofilament (pNF-H) and -tubulin, as well as the astrocyte marker glial fibrillary acidic protein (GFAP).
With severe or complete loss of transport to the SC (beginning at 8 months), large sections of the retina exhibited no CTB transport in axons still containing pNF-H or -tubulin. These often emanated from RGCs with intact CTB uptake. The reduction in axonal CTB in the retina was not global, as even with entirely depleted transport to the SC and optic tract, bundles of CTB+ axons in the retina and optic nerve head persisted. Retinal regions with complete depletion of CTB uptake and transport in RGCs demonstrated GFAP+ astrocytes containing CTB, whose number increased with age. At 12 months, transport to the SC failed completely, and an average of 23% of all CTB+ cells in the retina were identified as astrocytes (9.3-55.9%). With normal transport or modest deficits to the SC, CTB uptake was restricted to RGCs.
Depleted anterograde RGC transport appears first distally in the DBA/2J and precedes both overt axonal loss in the retina and optic nerve and deficits in RGC active uptake. As RGC uptake fails, astrocytes which normally do not take up CTB begin to do so. This is probably through the expression of the ganglioside receptor GM1, which has been linked to reactive astrogliosis in other diseases.
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