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Shuo Zhang, Polina Lyuboslavsky, Micah A Chrenek, Ilaria Piano, Kenkichi Baba, Gianluca Tosini, P. Michael Iuvone; Consequences of circadian clock disruption in the retina. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5044. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To test the hypothesis that retinal circadian clocks play critical roles in retinal light responses, visual function, and retinal morphology during development and aging.
We made a retina-specific knockout of Bmal1 in the retina using mice with a floxed Arntl gene and Chx10-Cre driver (rBmal1KO). We assessed retinal structure and function by spectral domain-optical coherence tomography (SD-OCT), electroretinography (ERG), optokinetic tracking, and immunofluorescence (ON bipolar cells: anti-PKCα, Gαo; cones: anti-arrestin-4, rhodamine-conjugated peanut agglutinin; photoreceptor terminals: PSD95).
rBmal1KO mice had lower contrast sensitivity as well as scotopic and photopic ERG b-wave amplitudes compared to controls. The lower scotopic b-wave amplitude was surprising, since, unlike the photopic ERG, the scotopic ERG is not regulated in a circadian manner. Strikingly, rBmal1KO mice failed to light adapt for at least up to 16 minutes when presented with a rod saturating background light. Assessed by SD-OCT, total retinal thickness, outer plexiform layer (OPL) thickness, and inner nuclear layer thickness were significantly lower in rBmal1KO mice at all ages compared to controls, and this effect became greater in the older mice. At 3 months of age, there was no difference between wild type and rBmal1KO mice in photoreceptor layer thickness. However, photoreceptor layer thickness was significantly lower in rBmal1KO mice at 1 and 2 years of age compared to wild type controls. Morphological analysis showed abnormalities in rod bipolar cells, consistent with lower OPL thickness and lower dark-adapted b-wave amplitude. These abnormalities were observed as early as 1 month of age, suggesting a developmental role of circadian clocks. Cone photoreceptor cell counts showed no differences between wild type and rBmal1KO mice at 3 months of age, but a significantly greater loss (~50%) of cones in 2-year old rBmal1KO mice.
These data indicate that circadian clock disruption in the retina has detrimental effects on retinal structure and function, which become more apparent with aging, and that circadian clocks play important roles in regulation of retinal development and cone photoreceptor viability during aging.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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