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Jeffrey Ma, M. Ali Shariati, Laura Pisani, Franco Pestilli, Bob Dougherty, Lee Michael Perry, Gun Ho Lee, Chris Contag, Brian A Wandell, Yaping Joyce Liao; Severe Impairment of Axonal Transport in Acute Experimental Anterior Ischemic Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6227. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Although retinal ganglion cells (RGCs) are gradually lost as part of normal aging, they degenerate rapidly following anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in adults over age 50. Identifying events that occur in RGCs early after acute ischemia may guide new therapies to salvage RGCs. In this study, we investigated the impact of ischemia on axonal transport using histology and in vivo using serial 7-Tesla manganese-enhanced magnetic resonance imaging (MEMRI).
We induced experimental AION using laser-assisted photochemical thrombosis in adult mice. To assess anterograde transport, we performed bilateral intravitreal injections of AlexaFluor488-conjugated cholera toxin B (CTB-A488) or manganese chloride (MnCl2) 2 hrs after inducing AION in one eye. We tracked transport at 24 hrs after AION by using histology/epifluorescent microscopy or 7-Tesla MRI, respectively, to measure fluorescence or contrast signal in the optic nerve, superior colliculus and lateral geniculate nucleus.
Within 24 hrs after AION, there was severe impairment of anterograde axonal transport of CTB-A488 along the optic nerve, as demonstrated by near complete loss of fluorescence in the contralateral superior colliculus (N = 19 mice, P <0.0001) and lateral geniculate nucleus (N = 10, P <0.01). Serial activity-dependent MEMRI confirmed a decrease in anterograde transport of manganese 24 hrs after AION (N = 4, P <0.05). This is similar to the effect of colchicine, a known microtubule inhibitor.
Acute optic nerve head ischemia is associated with severe impairment of anterograde axonal transport within 24 hours, which likely contributes to progressive axonal dysfunction and RGC death. Manganese-enhanced magnetic resonance imaging is a useful in vivo imaging modality for longitudinal visualization of transport defects. We demonstrated for the first time using MEMRI that axonal transport impairment is an important early event after experimental AION.
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