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Chad R. Jackson, Michael L. Risner, Guoxiang Ruan, Jane Abey, Fazila Aseem, Michael Iuvone, Douglas McMahon; Retinal Dopamine Is Required For Circadian Regulation Of Photopic Erg Amplitude. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3455.
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© ARVO (1962-2015); The Authors (2016-present)
The retinal dopaminergic system is important in light adapting the retina, as well as in coordinating its circadian parameters. This study was performed to determine if retinal dopamine affects the circadian regulation of retinal activity as measured by electroretinogram (ERG).
Genetically modified mice with floxed alleles of the tyrosine hydroxylase (TH) gene [Th(flox/flox)] were crossed with mice expressing Cre recombinase under the control of the Chx10 promoter (Chx10-Cre), selectively reducing retinal dopamine synthesis while leaving brain dopamine intact. HPLC and retinal cell ICC were used to assess retinal dopamine content. ERG responses were recorded at circadian times (CT) 6 or CT 18 in constant darkness, followed by photopic ERG recordings in which mice were exposed to bright light flashes on a rod-saturating background light. We assessed the circadian expression of the core clock protein PERIOD2 (PER2) by crossing retina-specific dopamine deficient mice with PER2::luciferase (PER2::LUC) mice and monitoring bioluminescence rhythms.
Cre-Th(flox/flox) mice showed an approximately 90% reduction in retinal dopamine content and in the number of TH-expressing amacrine cells (rDA-), while Cre-Th(flox/+) heterozygous displayed normal levels (rDA+). Scotopic ERG recordings showed no significant effect of CT or genotype on either b-wave or a-wave amplitudes. Under photopic conditions rDA+ mice showed significantly higher b-wave amplitudes at CT 6 than CT 18 over the entire 15 min of light adaptation; however, in rDA- mice this noticeable difference was absent between subjective day and night. Although the rhythms in photopic b-wave amplitude were lost in rDA- retinas, their molecular circadian clocks were still intact, with similar phase, amplitude and damping rate of PER2::LUC rhythms compared to rDA+ retinas.
We have developed a mouse model in which TH activity and dopamine are specifically disrupted in the retina. This mouse model provides evidence that while baseline ERG and circadian function are intact, the circadian modulation of the photopic ERG is disrupted in mice with reduced retinal dopamine. These data support the hypothesis that dopamine regulates the ERG downstream of retinal circadian clocks.
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