Morphological and functional abnormalities of retinal ganglion cells in STZ-induced diabetic mice

Abstract

Purpose : Retinal ganglion cell (RGC) death has been reported in retinas of diabetic patients and in diabetic animal models. However, morphological and functional alterations of RGCs in diabetic mice remain incompletely understood. Here we investigate changes in morphological and electrophysiological properties of several subtypes of RGCs in a diabetic mouse model.

Methods : Hyperglycemia was induced by intraperitoneal injection of streptozocin (STZ) in mice. Experiments were conducted in flat-mount retinas of mice 3 months after the induction of diabetes and in those of age-matched normal mice (control). Morphology of four subtypes of RGCs was examined in Thy1-YFP transgenic mice, in which RGCs were labeled with yellow fluorescent protein. Using whole-cell patch-clamp recording, electrophysiological properties of two subtypes of RGCs were analyzed in C57BL/6 mice.

Results : (1) Comparisons of the genetically identified RGCs in Thy1-YFP mice revealed that some subtypes underwent dramatic morphological modifications 3 months after the onset of diabetes. There was an increase in the amount of dendritic branches of both ON-RGA₂ and OFF-RGA₂ cells, whereas there was a decrease in dendritic field area in ON-RGA₂ cells in diabetic mice. RGD cells are bistratified cells and their dendritic arbors in the ON sublamina of the inner plexiform layer exhibited significant changes, but those in the OFF sublamina did not. In contrast, RGC₁ cells were structurally unaffected. (2) In the diabetic mice, transient ON-RGA₂ cells had an increased resting membrane potential (V_m) and a decreased membrane capacitance (C_m), whereas transient OFF-RGA₂ cells exhibited no differences in V_m and C_m. In these two subtypes of RGA₂ cells, maximum spike firing rate, maximum rate of depolarization and rate of repolarization were reduced, but action potential (AP) width was increased. Consistent to the changes in AP firing pattern, we found a decrease in outward potassium current density in these cells.

Conclusions : Morphological and functional alterations occurring in ON-, OFF-RGA₂ and RGD cells could, at least in part, mediate early stage retinal dysfunction of diabetes.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.