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Matthew A Smith, Denise M Inman, Christine M Dengler-Crish, Jerry Silver, Samuel D Crish; Synapse-like structures on retracting end-bulbs in the optic nerve of the DBA/2J mouse model of glaucoma. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2532.
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© 2017 Association for Research in Vision and Ophthalmology.
Axon degeneration in the optic nerve separates retinal ganglion cells from their major source of survival factors. Typically, disconnection of cells from their targets through axon transection produces extensive die-back and neurotrophin deprivation-mediated apoptosis. However, retinal ganglion cell somata in the retina and end-bulbs in the optic nerve persist for a significant period of time in the DBA/2J mouse model of glaucoma. Other neurodegenerations have proposed an “entrapment” phenomenon where end-bulbs form synapse-like interactions with glial cells within their tracts. The mechanism of this entrapment appears to include neuotrophin provision; ultimately, the interaction prevents regeneration. We identified end-bulbs in the DBA/2J optic nerve and examined them for synapse-like characteristics.
DBA/2J mice and DBA/2J-Gpnmb+ (control) mice received bilateral intravitreal injections of cholera toxin B (CTB). After seventy-two hours, animals were perfused and optic nerves were microdissected, longitudinally sectioned, and stained for the presynaptic density marker bassoon, the axonal marker heavy-chain neurofilament, and brain-derived neurotrophic factor (BDNF).
In both DBA/2J mice up to 9 months old and controls, end-bulbs within the optic nerve were rarely observed. We found very little bassoon immunoreactivity and evenly distributed BDNF staining along the length of these nerves. As previously reported, aged (14 month old) DBA/2J optic nerve exhibited a large number of end-bulbs characteristic of distal axonopathy. These end-bulbs consisted of large swellings showing accumulations of CTB and neurofilaments without any evidence of the axon extending beyond this structure. Within the bulbs, extensive bassoon-positive puncta on the surface of these end bulbs were located in close proximity to BDNF-positive cells. Importantly, bead-of-pearls type axonal swellings (CTB-positive varicosities along a continuous axon) did not exhibit bassoon-positive puncta, nor were they associated with BDNF-positive cells, indicating that the end bulb bassoon puncta were not merely accumulated cargo being transported along the axon.
These findings indicate that retracting RGC axons form synapse-like structures in the optic nerve—suggesting a possible mechanism that contributes to the somatic and axon segment persistence during pathology in this model.
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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