Role of circadian clock-controlled increase in GABA inhibitory feedback to cones at night

Abstract

Purpose : Following 30 min of darkness, repetitive mid-mesopic (= light intensity at dawn) stimulation for 5-20 min increases the cone ERG by ~50%, while the rod ERG is suppressed in seconds (Bui, Fortune, '06). This phenomenon, called “suppressive rod-cone interaction” (SRCI) (Eysteinsson, Frumkes, '89), occurs in many vertebrates including humans.Because 1) both light and the retinal circadian clock increase dopamine release, 2) GABA inhibitory feedback from horizontal cells to cones is strongest at night in the dark, reduces the size of cone light responses, depends on cone dopamine D₄Rs and GABA_ARs, and is suppressed by light (Mangel, '19, ARVO), and 3) rod-cone electrical synapses, which are regulated by the retinal clock, light stimulation, and D₄Rs, contribute to SRCI (Heikkinen et al., '11), we studied whether GABA inhibitory feedback to cones also mediates SRCI.

Methods : Using whole-cell patch-clamp recording of goldfish cones in the day and night, we studied the effects of 10 min of repetitive (0.1 Hz) full-field white light of various intensities, spiperone (SPI; D₄R antagonist), gabazine (GBZ; GABA_AR antagonist) and meclofenamic acid (MFA; gap junction blocker) on SRCI.

Results : After 30 min of darkness, repetitive mid-mesopic (but not low mesopic) stimulation increased cone light responses by ~55% at night but not in the day. Prior application of SPI for 30 min blocked SRCI at night. Also, after 30 min of SPI at night, 1) addition of MFA in the dark slightly increased cone response size and subsequent mid-mesopic stimulation further increased response size; and 2) addition of both MFA and GBZ in the dark increased cone response size to the same extent as 10 min of mid-mesopic stimulation and further light stimulation had no effect.

Conclusions : The results show that both the retinal circadian clock and background light modulate SRCI in a D₄R- and GABA_AR-dependent manner. When background light reaches the mid-mesopic level at dawn, it augments the clock-dependent decrease in GABA inhibition of cones, resulting in an enhancement of the increase in cone light response size. Conversely, the decrease in illumination below mid-mesopic at dusk enhances the decrease in cone light response size. Because rods do not express GABA_ARs in day or night, the synergistic effect of circadian and light on GABAinhibitory feedback to cones speeds up the transitions between rod and cone vision at dawn and dusk.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.