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Hee Joo Choi, Masaaki Ishii, Yu Cao, Adewunmi Adelaja, Christophe Ribelayga, Stuart C. Mangel; Retinal Circadian Clock Enhances GABAA Receptor-Mediated Horizontal Cell Feedback to Cones at Night, Compared to the Day. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6321.
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Because 1) GABAA receptor (GABAAR) expression and activity are increased when intracellular cAMP/PKA increases (Jacob et al., 2008) and 2) the circadian (24-h) clock in the retina increases intracellular cAMP/PKA in photoreceptor cells at night, compared to the day (Iuvone et al., 2005), we examined whether the GABAAR expression and activity of cones are increased at night, compared to the day.
Pigmented rabbits and goldfish were light (photopic)-adapted for 1 h in the day or dark (low scotopic)-adapted for 1 h in the day or night. Retinal sections were processed in an identical manner for immunostaining with specific antibodies against the β2/3 subunit-containing GABAAR (rabbits: bd-17; fish: 62-3G1) and the Cl-cotransporter KCC2 (B22). Double labeling with cell type-specific antibodies determined whether GABAARs and KCC2 are located on cone synaptic terminals (zpr-1) and bipolar cell (BC) (ON-BCs: Goalpha; OFF-BCs: GluR5) and horizontal cell (HC) (calbindin) dendrites. The effects of gabazine, a GABAAR antagonist, and spiperone, a D2R antagonist, on cones in intact goldfish neural retinas were studied in the day and night using whole-cell patch-clamp recording.
In both rabbits and fish, intense GABAAR and KCC2 antibody labeling were observed on cone terminals following prolonged dark adaptation at night, but not in the day following prolonged light or dark adaptation, and not on HC or cone-BC dendrites following prolonged dark adaptation at night. Gabazine increased the input resistance of goldfish cones at night, but had minimal effect on cones during the day following prolonged light or dark adaptation. During the night, repetitive light stimulation in the mid-mesopic range slowly increased cone responses to mid-mesopic stimuli over the course of several minutes, an effect that was blocked by spiperone.
The results suggest that GABAARs and KCC2 are expressed on cone synaptic terminals and are functional to a greater extent at night under dark-adapted conditions, compared to the day following either light or dark adaptation. The findings also suggest that the retinal clock, by elevating cAMP/PKA in cones at night, increases GABAAR and KCC2 expression, so that GABAAR-mediated feedback from HCs to cones is more effective at night, compared to the day. As light levels increase through the mesopic range at dawn, the decrease in GABAAR and KCC2 expression and activity of cones may preferentially enhance cone light responses. Conversely, as light levels decrease through the mesopic range at dusk, the increase in GABAAR and KCC2 expression and activity of cones may preferentially reduce cone light responses.
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