Inhibition in the retinal ON cone pathway is increased in early diabetes

Abstract

Purpose : There is increasing evidence of retinal neuronal dysfunction in early diabetes. We have previously shown that GABAergic inhibition is decreased in the rod pathway due to reduced GABA release from amacrine cells (AC). GABAergic AC dysfunction may occur across retinal pathways. The purpose of this study is to determine if GABAergic inhibition to cone bipolar cells (BC) is compromised in early diabetes.

Methods : Diabetes was induced in C57BL/6J, transgenic Mito-CFP and Gus-GFP mice by 3 i.p. injections of streptozotocin (STZ, 75mg/kg), and confirmed by blood glucose levels >200 mg/dL. Six weeks post injections, AC function in the cone pathway was tested by recording light-evoked (L) IPSCs from OFF and ON BCs in dark-adapted retinal slices in response to a 30ms full-field light stimulus. Receptor (R) inputs were pharmacologically isolated. The peak amplitude, charge transfer and time to decay to 37% of peak (D37) were measured.

Results : The charge transfer of ON BC L-IPSCs was significantly increased at multiple intensities in diabetic mice (n=11 cells) compared to control mice (n=10, p<0.05). ON BC L-IPSCs from diabetic mice had a slower D37 (p<0.05). Isolated GABA_AR-mediated L-IPSCs in diabetic mice (n=3) had on average increased charge transfer and longer D37 compared to control (n=3). There was no significant difference in GABA_CR-mediated L-IPSC peak amplitude and charge transfer between control (n=5) and diabetic mice (n=5). In the OFF pathway, the D37 of OFF BC L-IPSCs was significantly slower at multiple intensities in diabetic mice compared to control (n=12 for both, p<0.05).There was no significant difference in GABA_AR-mediated L-IPSCs of OFF BCs.

Conclusions : Unlike in the rod pathway, inhibition in the cone pathway is increased in early diabetes. In OFF BCs, the slower timing of L-IPSCs was likely due to a change in glycinergic signaling, since there was no difference in isolated GABA_AR-mediated L-IPSCs. In ON BCs, elevated inhibition is likely due to increased GABA_AR-mediated inhibition, since there is no change in GABA_CR-mediated inhibition and ON BCs do not express glycine Rs. These results show that aberrant amacrine cell signaling differs across retinal pathways and may underlie changes in retinal electrical signaling in diabetes.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.