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Editors Selection IGR 8-2

Basic Science: Neuroprotection 2

Comment by Brad Fortune on:

67276 Axonal transport along retinal ganglion cells is grossly intact during reduced function post-injury, Fahy ET; Chrysostomou V; Abbott CJ et al., Experimental Eye Research, 2016; 146: 289-292

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This recent brief report by Fahy et al. found that when young or older mice were exposed to an acute episode of elevated intraocular pressure (IOP, 50 mmHg for 30 minutes in one eye), there was no effect on axonal transport assessed five to seven days later. In their study, the investigators evaluated bulk anterograde axonal transport using bilateral intravitreal injections of fluorescently labeled cholera toxin beta (CTB) and post-mortem microscopic images of the superior colliculi obtained 48 hours after CTB injection. This assay works in C57BL/6J mice (and in pigmented rats, as had been shown previously) because > 95% of retinal ganglion cell (RGC) axons cross to synapse in the contralateral superior colliculus. Thus, the integrity of anterograde axonal transport for a given optic nerve can be compared to the fellow eye optic nerve by comparing fluorescence between the right and left superior colliculi. The investigators confirm this in a pair of control experiments in which CTB was either omitted from the injection in one eye or was injected after pre-treatment by intravitreal injection of colchicine to disrupt microtubules and axonal transport. In both cases, there was a gross asymmetry of fluorescence intensity across hemispheres of the superior colliculus. In contrast, when young (age three months, N = 8) or older mice (18 months, N = 8) were exposed to 30 minutes of 50 mmHg in one eye, there was no defect of anterograde axonal transport evident in either group when assayed five to seven days later. This result is interesting in the context of previous results published by this group¹ which demonstrated substantial reduction at the same time point of the electroretinogram feature known as the positive scotopic threshold response (pSTR), a signal known to depend on intact RGC function. Moreover, the results of that previous ERG study showed a clear age effect in that older mice experienced a larger decline and less recovery of the pSTR specifically after the same IOP challenge. This apparent contrast was highlighted by the authors as one of prominent findings of their newer axonal transport study: "Impaired recovery of inner retinal function 1 week following acute IOP injury in old mice is not associated with changes in active axonal transport in RGCs at this time." Further: "Our results suggest that significant RGC electrical dysfunction can occur under conditions of normal axonal transport." It should be noted, however, that no ERG recordings were made during the present study on axonal transport, so the comparison is limited to historical results. Similarly, the previous ERG study did not include RGC or axon counts to document what degree, if any, of anatomical loss was associated with the marked functional deficit following this acute, sub-ischemic episode of acute IOP elevation. It is perhaps even more interesting if such functional loss occurs without any neuronal loss, nevertheless it should stimulate further exploration and explanation.

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