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Johnnie Moore-Dotson, Reece Mazade, Adam Berstein, Melissa Romero-Aleshire, Heddwen Brooks, Erika Eggers; Retinal Inhibitory Signaling is Increased in Streptozotocin-induced Diabetes. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5093.
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© ARVO (1962-2015); The Authors (2016-present)
Clinical characteristics of diabetic retinopathy include vascular changes that cause retinal edema. However, recent studies have shown changes in retinal signaling prior to the onset of vascular changes that reflect altered GABAergic signaling. The purpose of this study is to determine whether GABAergic signaling between neurons of the inner retina is increased in a mouse model of diabetes.
At 5 weeks of age C57BL/6J mice were injected i.p. with streptozotocin (STZ, n= 16 mice) or control vehicle citrate buffer (n= 16 mice). Diabetes was confirmed by blood glucose levels >200 mg/dL. Six weeks post injections, whole-cell voltage clamp recordings of spontaneous inhibitory post synaptic currents (sIPSC) were made from rod bipolar cells (BCs) in dark adapted mouse retinal slices. Rod BCs were held at the reversal potential for cation-mediated currents to isolate sIPSCs. GABAA and GABAC receptors (R) were isolated with strychnine (500 nM), SR95531 (20 µM) and bicuculline (50 µM). A high K+ (15 mM) solution was used to increase GABA release onto GABACRs.
The average peak amplitude of GABAAR sIPSCs was significantly increased in STZ mice (18.01 + 3.9 pA , p < 0.05, n=16 cells) compared to control (9.01 + 1.3 pA, n = 14). The frequency of GABAAR (Control: 0.233 + 0.09, STZ: 0.44 + 0.20 Hz, p = 0.35) and GABACR (Control: 0.193 + 0.06, STZ: 0.45 + 0.11 Hz, p = 0.07) events trended towards higher values in STZ mice. There was no correlation between elevated blood glucose levels and the frequency of GABAAR and GABACR sIPSCs. The average peak amplitude of GABACR (R2 = 0.28) sIPSCs was weakly correlated with elevated blood glucose in STZ mice.
These results suggest that inhibitory input to rod BCs is increased in the STZ mouse model of diabetes. The increase in the peak amplitude of GABAAR sIPSCs may reflect an increase in the amount of GABAARs. The elevated frequency of both GABAAR and GABACR events suggest an increase in spontaneous GABA release from amacrine cells. We did not find a strong correlation between the blood glucose levels in STZ mice and peak amplitude or frequency of sIPSCs. This suggests that elevated blood glucose above the threshold of diabetes does not further increase GABA currents. These results are consistent with an increase in GABAergic inhibitory signaling and likely contribute to the changes in retinal electrical signaling that occurs in diabetic retinopathy.
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