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Bruce Berkowitz, Timothy Kern, Vladimir Kefalov, Johannes Von Lintig, Robin Roberts, David Bissig; Impaired Chromophore Availability in the Diabetic Retina: Impact on Visual Performance. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2680. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To test the hypothesis that subnormal intraretinal ion channel activity and visual performance measured in diabetic mice are due to inadequate availability of chromophore.
Diabetic and non-diabetic age-matched C57Bl/6 mice and rd12 mice (RPE65 mutant) were dark adapted for either 1 day (1dDA) or 5 days (5dDA). 5dDA groups: controls (without or with matrigel s.q.) or treated (matrigel and 9-cis-retinal (PMID: 20574023) mice. Intraretinal L-type voltage gated calcium channel (VGCC) activity in vivo was evaluated using manganese-enhanced MRI (MEMRI). Spatial frequency threshold (SFT) and contrast sensitivity (CS) were measured with optokinetic tracking. Parallel ex vivo transretinal electrophysiological studies were also performed from 1dDA mice. A subset of the diabetic retinas was treated with 100 µM 11-cis retinal prior to recordings. Steady-state levels of 11-cis-retinal, all-trans-retinal, and retinyl esters were also measured.
In 5dDA controls, retinal VGCCs on MEMRI are not sustained in the open position (i.e., they are closed or “dark desensitized”) but were opened upon treatment with the chromophore surrogate 9-cis-retinal. However, visual performance did not decrease following extended darkness and was not altered by 9-cis-retinal treatment. In contrast, overnight dark adapted diabetic mice (before the appearance of microangiopathy) had inappropriately closed photoreceptor L-VGCCs on MEMRI which partly opened with five days of darkness. The ion channels in photoreceptors from diabetic mice were regulated by darkness in a manner similar to that in normoglycemic rd12 mice (an “equivalent light” model). Ex vivo transretinal ERG sensitivity was reduced about 2-fold in diabetic mice (and accordingly, I1/2 is increased about 2-fold). The effects were largely reversed by the application of 11-cis retinal. Changes in retinoid metabolism (particularly chromophore production) were found consistent with increased production of free opsin. In vivo, 5dDA diabetic mice treated with 9-cis-retinal had significantly opened outer retinal channels (MEMRI) and corrected diabetic visual impairment.
Diabetes-evoked reduction in photoreceptor chromophore availability contributes to the associated visual performance dysfunction.
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