Hyperactivity preferentially disrupts scotopic retinal circuits in the early stages of diabetic retinopathy

Diabetic retinopathy is a leading cause of blindness worldwide. In this disease, visual impairments result from neurovascular dysfunction in the retina. However, the specific retinal circuits and the mechanisms underlying their dysfunction remain unclear. Here, in mouse models of diabetes, we evaluated scotopic (night vision) and photopic (day vision) retinal circuit function in the early stages of the disease. Using a combination of immunohistochemical, behavioral and electrophysiological techniques, we show that vision impairments early in the disease are not associated with widespread degeneration of the retinal circuitry but with abnormalities localized to scotopic circuits. Specifically, we observed swelling of axon terminals in rod but not cone bipolar cells. Importantly, these abnormalities were closely linked with bipolar cell activity, as rod bipolar cells showed higher intrinsic activity than cone bipolar cells, and inducing hyperactivity in control retinas was sufficient to recapitulate the pathology in diabetic rod bipolar cells. Further, the swollen rod bipolar cell terminals exhibited an increase in oxidative stress, consistent with cellular dysfunction. In line with this notion, electrophysiological measurements demonstrated that the contrast sensitivity of retinal ganglion cells was preferentially attenuated under scotopic conditions. Finally, behavioral experiments showed that visual sensitivity under scotopic conditions was affected earlier in disease progression compared to photopic conditions. Together, these findings reveal that scotopic circuits are preferentially affected in the early stages of diabetic retinopathy and that hyperactivity is sufficient to drive these abnormalities.