Modulation of the GABA signaling pathway in the diabetic retina

Changes in neurosensory function accompany diabetes. Alterations in the oscillatory potentials (OPs) of the electroretinogram (ERG) are one of the most consistent findings in both patients with diabetes and animal models of the disease and are suggestive of a compromise of the GABAergic mechanisms of the inner retina. Despite evidence that the GABA signaling pathway is altered in diabetes, no study has investigated the modulation of the activity of retinal neurons in the diabetic retina directly. To examine the basic biological mechanisms of these changes in retinal function, I examined the onset and progression of electroretinographic changes in female streptozotocin (STZ)-induced diabetic rats and recorded the GABA-induced responses of individual rod bipolar cells isolated from their retina. Compared to previous reports of the effects of diabetes in male rats, the abnormalities in visual function appear to be milder in STZ-treated female rats, indicating a gender dimorphism in visual function in the rat. However, diabetic females, like their male counterparts, did show significant differences in pattern of the OPs. I found that the GABA responses of bipolar cells and the GABA distribution within the retina were significantly altered in diabetic rats. Membrane current recordings from isolated bipolar cells indicated that the GABAC receptor-mediated responses from diabetic animals exhibited a greater sensitivity and larger maximum currents to the application of GABA than those derived from control rats. Although the overall expression of GABAC receptors was slightly reduced in diabetic retina, the GABA responses of individual bipolar cells were nonetheless enhanced. Real time RT-PCR analysis of gene expression, combined with the analysis of the biophysical properties of the GABAC receptors on retinal bipolar cells, suggest that a change in the composition of the GABA C receptors is likely to be occurring in the diabetic retina. Most importantly, my results suggest that changes in the GABA-signaling pathway may be the underlying cellular mechanism for altered ERG responses in diabetes. Recognition of these early neurosensory defects will enable us to better understand the pathophysiological basis of diabetic retinopathy, and also provide a foundation for developing new therapeutic approaches to treat diabetic patients.