Retinal Light Adaptation and Dopaminergic Signaling in Early Diabetes

Throughout the course of a day, our eyes are exposed to an enormous range of environmental light intensities. In order to maintain proper visual function, the retina dynamically modulate its own light sensitivity to match current luminance conditions. The various neural mechanisms involved in this modulation are collectively termed, ‘light adaptation’. A key neuromodulator involved in light adaptation is the catecholamine dopamine. Dopamine is produced by a specialized class of amacrine cell in the retina and is released in a paracrine manner when ambient illumination exceeds a certain threshold. By binding to its receptors on various retinal populations, dopamine induces changes in retinal network activity that optimize acuity, color and speed over sensitivity. Although it is known that dopamine is important to light-adapted vision, the various mechanisms through which it reorganizes retinal circuitry have not yet been thoroughly investigated. In recent decades, a dopamine deficiency has been implicated in the subtle visual deficits that occur in early diabetes. Available evidence from clinical data and rodent studies suggest a selective disruption to inhibitory signaling in the dim-light rod pathway. These changes occur long before the presentation of the more severe symptoms associated with diabetic retinopathy, suggesting a possible causative link. The main goals of this dissertation were to 1) assess the contribution of different dopaminergic pathways to light adaptation, and 2) determine if dopamine release or signaling is disrupted in early diabetes. To do so we measured the effects of dopamine receptor agonists and light adaptation on inhibitory and excitatory currents in neurons of the rod pathway. We found that in wild-type retinas D1R activation decreases inhibitory inputs to rod bipolar cells, but not to the same extent as light adaptation. We also found that activating D1Rs or D4Rs, or light adaptation decreased excitatory inputs to ON sustained ganglion cells, but light adaptation had a larger impact than stimulation of either receptor. We then repeated these experiments in control and diabetic retinas. We found that reductions in rod bipolar cell inhibition upon D1R activation or light adaptation occurred equally in control and diabetic animals, suggesting unimpaired dopamine release and signaling through D1Rs. At the ganglion cell level we showed that light adaptation and D4R activation did not reduce excitatory currents in diabetic cells as much as it did in controls. This suggests that an impairment in dopaminergic signaling to photoreceptors, and possibly ganglion cells, underlies changes in retinal contrast sensitivity in early diabetes. Lastly, we confirmed some of our single-cell findings via ERG measurements, showing that photoreceptor and bipolar cell adaptation to bright lights is impaired in early diabetes