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Editors Selection IGR 14-4

Basic Science: Can Insulin be neuroprotective for RGCs?

Comment by James Morgan on:

Our understanding of the processes underpinning retinal ganglion cell degeneration in glaucoma has changed considerably in recent years. Evidence from animal models and human studies indicates that retinal ganglion cell (RGC) death in glaucoma is preceded by dendritic degeneration, likely occurring before axon loss. In a landmark study, Hajji et al. explore whether dendrite remodelling can be used as a neural substrate for the reversal of retinal ganglion cell damage in glaucoma. If dendritic structure can be restored, vision could be recovered and RGC death prevented.

They use a mouse model of glaucoma in which the iridocorneal angle was blocked using magnetic microbeads to elevate the intraocular pressure (OHT). For RGC recovery they applied topical insulin (eye drops) to stimulate mTORC (mammalian target of rapamycin complex), an important factor in maintaining neuronal dendritic integrity. RGC dendrites were traced using the genetically expressed label, YFP. They demonstrate significant dendritic degeneration following OHT, which could be reversed following the application of topical insulin (treatment was started after the onset of RGC degeneration); this reversal in degeneration was not observed following the reduction in IOP. Critically, they confirm elevated insulin levels in the vitreous and retina following treatment. In a series of intricate experiments knocking down effector molecules they show that SIN1 (a stress induced protein) mediated linked mTORC1 and 2 activities in a positive feedback process to enhance dendritic remodelling. Dendritic recovery was associated with restoration of pre and post synaptic connectivity, laying the foundation for a recovery in visual function as demonstrated in this model by enhanced oculomotor responses.

The results are exciting since they support the concept that vision can be recovered in glaucoma. Insulin treatment is associated with increased RGC survival, but we do not yet know how RGC afferent connections are affected and how this might influence higher level visual responses. Since dendritic pruning could be an adaptive response to damage, forcing the recovery of dendrites could increase cell stress and increase the risk of axon loss(1). While this does not appear to be the case in this study of short-term OHT in mice, further careful study will be required to confirm that this is the case with long-term glaucoma in man.

The results are exciting since they support the concept that vision can be recovered in glaucoma

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