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Robin Roberts, Alana Conti, Bruce Berkowitz; Mice lacking Adenylyl Cyclase (AC) 1 and 8 Mimic Supernormal Intraretinal Ion Channel Activity in Light-adapted Diabetic Mice But have No Impairment in Visual Performance. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5556.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetes significantly decreases retinal AC activity (Diabetologia 35; 624 (1992)), the major modulator of retinal cyclic AMP (cAMP) production, although the functional significance of this change remains unclear. Here, we tested the hypothesis that the abnormal intraretinal ion channel activity and visual performance measured in diabetic mice are recapitulated in non-diabetic mice lacking AC 1 and 8.
The following groups were studied: dark- and light-adapted 2-3 mo diabetic and non-diabetic age-matched wildtype (WT) C57Bl/6 mice, and dark- and light-adapted non-diabetic AC 1 and 8 double knockout mice (DKO, C57Bl/6 background). Retinal VGCC activity in vivo was measured using manganese-enhanced MRI (MEMRI) T1 mapping with and without pretreatment with the calcium channel antagonist diltiazem. Spatial frequency threshold (SFT) and contrast sensitivity (CS) were measured with optokinetic tracking.
As expected, non-diabetic dark-adapted WT mice had greater uptake in the outer retina than light-adapted mice, whereas no adaptation differences were noted in inner retina. In diabetic mice, intraretinal uptake was subnormal (P < 0.05) with dark-adaptation, but supernormal (P < 0.05) with light-adaptation. In DKO mice, outer retinal uptake was not different (P > 0.05) between dark- and light-exposure, and with that in dark-adapted WT mice. On the other hand, inner retina uptake was significantly (P < 0.05) greater in the light than in the dark and was supernormal (P < 0.05) with light-adaptation. Pre-treatment with diltiazem fully corrected this supernormal inner retinal uptake in DKO mice. Compared to non-diabetic WT mice, SFT and CS were both reduced (P < 0.05) in the diabetic but not (P > 0.05) DKO mice.
Based on the DKO data, the major effect of a diabetes-evoked decrease in AC levels per se may be limited to modulation of inner retinal L-type voltage gated calcium channel activity during light adaptation and not decreased visual performance. These data raise the possibility that retinal cAMP plays a minor role in early diabetic pathophysiology.
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