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D. J. Ramsey, H. Ripps, H. Qian; Diabetes Modulates GABA Receptor Activity on Rat Retinal Neurons. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4587.
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© ARVO (1962-2015); The Authors (2016-present)
Neural deficits suggestive of involvement of the GABA signal pathway can often be detected early in the course of diabetic retinopathy, a leading cause of blindness in the United States. However, there is little knowledge about the effects of hyperglycemia on the properties of GABA receptors present on retinal neurons. In this study, we investigated GABA receptor activity on retinal bipolar cells in streptozotocin-induced diabetic rats.
Pigmented Long Evans rats received 60 mg/kg streptozotocin IV dissolved in 0.9% Na citrate buffer (pH 4.5). Diabetes was established by demonstrating a blood glucose level over 350 mg/dl. Animals were sacrificed between 8 and 24 weeks. The whole cell patch clamp recording was used to monitor the membrane current from individual rod-bipolar cells isolated from rat retina. Real-time RT-PCR was used to measure the expression level of GABA rho subunits in tissue samples from control and diabetic retina.
GABA elicited larger currents on rod-bipolar cells isolated from diabetic retina (319 ± 9 pA) than those from age-matched controls (217 ± 8 pA). A similar enhancement was also observed for the GABAC receptor-mediated responses (256 pA vs 171 pA for diabetic and control bipolar cells, respectively). In addition, the GABAC receptor-mediated responses on diabetic cells exhibit slower kinetics with GABA inactivation time constants of 1.77 seconds vs 1.57 seconds for control. Noise analysis was used to estimate the single channel conductances for the GABAC receptor, and the averaged values were 0.94 pS for diabetic cells and 1.26 pS for normal cells. Comparing these results with the properties of homomeric and heteromeric rho receptors formed in HEK cells suggested that diabetes altered the subunit composition of the GABAC receptors on bipolar cells. Real-time RT-PCR was used to measure the levels of mRNA for GABA rho subunits expression in the retina. While the levels of GABA rho1 subunit expression were comparable in diabetic and normal retinas, there was a significant enhancement in the ratio of rho1/rho2 subunit expression in the diabetic animals.
Diabetes modulates the GABAC receptor properties on retinal bipolar cells, most likely through alterations in the gene expression of the receptor subunits. These modifications, in combination with other changes in GABAergic pathway, could underlie the observed early neurosensory defects detected in diabetic patients.
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