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Johnnie Moore-Dotson, Reece Mazade, Adam Bernstein, Melissa Romero-Aleshire, Heddwen Brooks, Erika D Eggers; Amacrine cell dysfunction in early diabetes. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3229.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy is clinically defined by unregulated vascular growth and retinal edema. However, recent studies have shown that amacrine cell function is compromised in diabetes before vascular retinal damage. We previously found dysfunction in GABAergic amacrine cell signaling to rod bipolar cells, but it is not known how diabetes affects the output of the rod pathway or inhibition in the cone pathway. The purpose of this study is to determine if rod bipolar cell output to AII amacrine cells and inhibition to cone bipolar cells are compromised in early diabetes.
Diabetes was induced in C57BL/6J, transgenic Mito-CFP and Gus-GFP mice by 3 i.p. injections of streptozotocin (STZ, 75 mg/kg), and confirmed by blood glucose levels >200 mg/dL. Six weeks post injections whole-cell voltage clamp recordings of light-evoked (L) and spontaneous (s) inhibitory (IPSCs) and excitatory postsynaptic currents (EPSCs) were made from AII amacrine cells (ACs) and OFF and ON cone bipolar cells (BCs) in dark adapted retinal slices. Cells were held at the reversal potential for Cl- ions to isolate EPSCs or the reversal potential for cations to isolate IPSCs. A 30ms full field LED stimulus was used to elicit light responses. Receptor (R) inputs were pharmacologically isolated. The peak amplitude and charge transfer (Q) were measured for light responses. The peak amplitude and frequency were measured for sPSCs.
The frequency and peak amplitude of AII AC sEPSCs were increased in STZ mice (n=6 cells, p<0.001) compared to control (n=6). The peak amplitudes of AII ACs L-EPSCS in STZ mice were on average higher but not significantly different (p=0.3). In the cone pathway, sIPSCs of OFF (n=6) and ON BCs (n=5) from STZ mice had reduced peak amplitudes and frequency (p<0.001). Isolated GABAAR sIPSCs of OFF BCs from STZ mice (n=3) had reduced peak amplitudes and frequency compared to control (n=3, p<0.001). There was no difference in the L-IPSC peak amplitude of OFF BCs between control (n=4) and STZ mice (n=5, p=0.6), although it was on average higher in STZ mice.
Elevated excitatory activity of AII ACs suggest increased output from the rod pathway. Altered inhibitory signaling to cone BCs suggest changes in AC function. These results show that AC-BC signaling is altered in the rod and cone pathways in early diabetes, and likely contributes to changes in retinal electrical signaling that occurs in diabetic retinopathy.
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