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Stuart Mangel, Hee Joo Choi, Masaaki Ishii, Yu Cao, Adewunmi Adelaja, Jiexin Cao, Christophe Ribelayga; Role of Circadian Clock-Induced Enhancement of GABAA Receptor-Mediated Feedback to Cones at Night. Invest. Ophthalmol. Vis. Sci. 2013;54(15):404.
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Because GABAAR expression and activity increase when intracellular cAMP increases (Luscher et al., 2011) and the retinal circadian clock, by activating the dopamine D2Rs of cones in the day, increases intracellular cAMP in cones at night compared to the day (Iuvone et al., 2005), we studied 1) whether the GABAAR expression and activity of cones increase at night compared to the day and 2) the function of this day/night difference.
Rabbits and goldfish were light-adapted for 1 h in the day or dark-adapted for 1 h in the day or night. Retinal sections were processed in an identical manner with specific antibodies against the β2/3 subunit of GABAARs (rabbits: bd-17; fish: 62-3G1). Double labeling with cell type-specific antibodies determined whether GABAARs are located on cone pedicles (rabbits: PNA; fish: zpr-1) and ON-bipolar cell (BC) (Goα) and horizontal cell (HC) (calbindin) dendrites. The effects of spiperone, a D2R antagonist that increases cAMP in cones, and gabazine, a GABAAR antagonist, on cones in fish retinas were studied in the day and night using whole-cell patch-clamp recording.
In horizontal sections through cone pedicles and in vertical sections, intense GABAAR antibody labeling was observed on cone terminals following prolonged darkness at night, but not in the day following light or dark adaptation, and not on HC or cone-BC dendrites following prolonged darkness at night. Gabazine increased the input resistance of fish cones at night, but had minimal effect in the day. Mid-mesopic light stimulation for 5 min at night increased cone response size by 50%, an effect that was blocked by spiperone but which occurred in the presence of both spiperone and gabazine.
The results suggest that 1) GABAARs are expressed on cone pedicles and functional to a greater extent at night in the dark, compared to the day following light or dark adaptation, and 2) the retinal clock, by elevating cAMP in cones at night, increases GABAAR expression, so that GABAAR-mediated feedback to cones is more effective at night than in the day. As cAMP levels in cones decrease at dawn due to increased D2R activation by the clock and/or by mid-mesopic light, the decrease in GABAAR expression and activity of cones may enhance the size of cone light responses. Conversely, as cAMP levels increase at dusk, the increase in GABAAR expression and activity may reduce cone light response size.
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