Morpho-functional analysis of the early changes induced in retinal ganglion cells by the onset of diabetic retinopathy: The effects of a neuroprotective strategy

Purpose: Retinal ganglion cells (RGCs) are highly susceptible to diabetes-induced metabolic stress. This study describes the early responses of RGCs to hyperglycemia and examines the effects of the neuroprotective somatostatin analog octreotide (OCT). Methods: Thy1-green fluorescent protein (GFP)-M transgenic mice were used, which express GFP in a number of RGCs. OCT was intravitreally injected in mice with streptozotocin (STZ)-induced diabetes. A longitudinal electroretinography (ERG) analysis was performed up to 2 weeks from STZ treatment. RGC density was measured and extensive morphometric analyses were performed on identified RGC subtypes. Results: STZ treatment caused a decline of RGC function, which was counteracted by OCT. No differences in RGC density were recorded, indicating that impaired activity was unlikely to be related to RGC death. Different GFP-labeled RGC subtypes were identified and analyzed. Overall, large RGCs were mostly affected by diabetes and responded to OCT treatment, while those with smaller dendritic arborizations were less involved. Interestingly, depending on the complexity of the dendritic tree, OCT could completely rescue RGC morphometric parameters or increase the effects of hyperglycemia. Conclusions: There is an early response of RGCs to diabetes, which involves specific morpho-functional deficits but not overt cell death. OCT induces adaptive changes that, although different among RGC subtypes, contribute to RGC functionality in the presence of metabolic stress. These results highlight the importance of neuronal protection in the early phases of diabetic retinopathy, when cell loss has not yet started and RGC morphology can be preserved or adjusted to maintain RGC physiology.