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S. D. Crish, P. Balaram, D. M. Inman, P. J. Horner, D. J. Calkins; Early Transport Deficits and Distal Axonopathy in the DBA/2J Mouse Model of Pigmentary Glaucoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3664. doi: https://doi.org/.
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Glaucoma is a neurodegenerative disease characterized by sensitivity to intraocular pressure (IOP) and loss of retinal ganglion cell bodies and their axons in the optic nerve. In other neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease axon transport deficits and distal axonopathies are early injuries. In glaucoma, axon transport deficits have been found at the optic nerve head (ONH) in response to acute elevations in IOP, and recent evidence suggests that axon degeneration in the nerve is also an early component. However, it is not known whether in glaucoma, as in other neurodegenerations, there is also an earlier axonal dysfunction in the distal projection to the brain. We tested this hypothesis by examining active anterograde axonal transport from the retina to the superior colliculus in the DBA/2J mouse a model of hereditary glaucoma.
The neuronal tracer cholera toxin β-subunit (CTB) was injected intravitreally in 3, 5, 8, 10, 12, 15, and 18 month old DBA/2J mice. Forty-eight hours later the animals were sacrificed and their brains and optic nerves were prepared for histological examination. We determined the distribution of transport to the superior colliculus (SC) - the major target of rodent RGCs - and examined the optic nerve, optic tract, and layer III of the SC for evidence of transport blockade and degeneration.
Animals at all ages could exhibit pathology in the optic nerve and brain. In the retinotopic map of the SC we found that the deficits were not uniform, but occurred in discrete regions associated with the optic disc gap (the collicular representation of the optic nerve head), either beginning peripherally and "traveling" to the gap, or joining it. Older animals tended to exhibit more severe deficits. Animals older than 10 months of age had no detectable transport to any portion of the SC. The transport deficits did not correlate with magnitude of IOP before sacrifice (r2=0.02). Further evidence that these transport deficits were not acute was that in layer III of the SC, the optic tract, and the optic nerve CTB-positive axonal dystrophies were evident. These took two different forms: either evenly spaced spheroids characteristic of transport blockade, or end bulbs which indicated either a distal wallerian degeneration or a "dying back" type degeneration.
Our data indicate that pathology begins early in the DBA/2J mouse, with the first site of injury in the distal retinal projection.
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