Impaired Light Adaptation of ON-Sustained Ganglion Cells in Early Diabetes Is Attributable to Diminished Response to Dopamine D4 Receptor Activation

Abstract

PURPOSE. Retinal neuronal signaling is disrupted early in diabetes, before the onset of the vascular pathologies associated with diabetic retinopathy. There is also growing evidence that retinal dopamine, a neuromodulator that mediates light adaptation, is reduced in early diabetes. Previously, we have shown that after 6 weeks of diabetes, light adaptation is impaired in ON-sustained (ON-s) ganglion cells in the mouse retina. The purpose of this study was to determine whether changes in the response to dopamine receptor activation contribute to this dysfunction. METHODS. Single-cell retinal patch-clamp recordings from the mouse retina were used to determine how activating dopamine type D4 receptors (D4Rs) changes the light-evoked and spontaneous excitatory inputs to ON-s ganglion cells, in both control and 6-week diabetic (STZ-injected) animals. Fluorescence in situ hybridization was also used to assess whether D4R expression was affected by diabetes. RESULTS. D4R activation decreased light-evoked and spontaneous inputs to ON-s ganglion cells in control and diabetic retinas. However, D4R activation caused a smaller reduction in light-evoked excitatory inputs to ON-s ganglion cells in diabetic retinas compared to controls. This impaired D4R signaling is not attributable to a decline in D4R expression, as there was no change in D4R mRNA density in the diabetic retinas. CONCLUSIONS. These results suggest that the cellular response to dopamine signaling is disrupted in early diabetes and may be amenable to chronic dopamine supplementation therapy.