Early Functional and Morphologic Abnormalities in the Diabetic Nyxnob Mouse Retina

PURPOSE. The electroretinogram c-wave is generated by the summation of the positive polarity hyperpolarization of the apical RPE membrane and a negative polarity slow Pill response of Miller glia cells. Therefore, the c-wave reduction noted in prior studies of mouse models of diabetes could reflect a reduction in the RPE component or an increase in slow Pill. The present study used a genetic approach to distinguish between these two alternatives. MFTHODS. Nyx(nob) mice lack the ERG Nyx(nob), revealing the early phase of slow PIII. To visualize changes in slow Pill due to diabetes, Nyx(nob) mice were given streptozotocin (STZ) injections to induce diabetes or received vehicle as a control. After 1, 2, and 4 weeks of sustained hyperglycemia (>250 mg/dL), standard strobe flash ERG and dc-ERG testing were conducted. Histological analysis of the retina was performed. RESULTS. A reduced c-wave was noted at the 1 week time point, and persisted at later time points. In comparison, slow PIII amplitudes were unaffected after 1 week of hyperglycemia, but were significantly reduced in STZ mice at the 2-week time point. The decrease in amplitude occurred before any identifiable decrease to the a-wave. At the later time point, the a-wave became involved, although the slow Pill reductions were more pronounced. Morphological abnormalities in the RPE, including increased thickness and altered melanosome distribution, were identified in diabetic animals. CONCLUSIONS. Because the c-wave and slow PIII were both reduced, these results demonstrated that diabetes-induced reductions to the c-wave cannot be attributed to an early increase in the Muller glia-derived potassium conductance. Furthermore, because the a-wave, slow PIII and c-wave reductions were not equivalent, and varied in their onset, the reductions cannot reflect the same mechanism, such as a change in membrane resistance. The presence of small changes to RPE architecture indicate that the c-wave reductions present in diabetic mice likely represents a primary change in the RPE induced by hyperglycemia.