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.

Visual Dysfunction in Diabetes

“…Lower levels of dopamine in the rodent diabetic retina reduce light-evoked dopamine release ( Nishimura & Kuriyama 1985 ) and light adaptation of a type of ganglion cell ( Flood et al 2020 ) after 3–6 weeks of diabetes. D4R modulation of light-evoked ganglion cell signaling is also reduced after 6 weeks of diabetes, independent of changes in D4R mRNA expression ( Flood et al 2022 ). Since the effect of dopamine on retinal neurons is to decrease sensitivity to light, reducing the effects of light adaptation causes retinal ganglion cells to be overexcited after light adaptation.…”

Retinal Neurodegeneration in Euglycemic Hyperinsulinemia, Prediabetes, and Diabetes

“…So dopamine supplementation is suggested as a potential treatment for diabetic patients before the clinical presentation of DR [99]. In summary, multiple changes occur in the dopaminergic pathway in DR. Dopaminergic cells of the retina die in DR [100], sensitivity to dopamine receptors decreases [99], and the loss of this neurotransmitter is associated with both vasculopathy and neurodegeneration in DR [101]. Supplementary dopamine can even reverse visual dysfunction in early DR [5, 102].…”