Dopamine-Mediated Circadian and Light/Dark-Adaptive Modulation of Chemical and Electrical Synapses in the Outer Retina

Abstract

The vertebrate retina, like most other brain regions, undergoes relatively slow alterations in neural signaling in response to gradual changes in physiological conditions (e.g., activity changes to rest), or in response to gradual changes in environmental conditions (e.g., day changes into night). As occurs elsewhere in the brain, the modulatory processes that mediate slow adaptation in the retina are driven by extrinsic signals (e.g., changes in ambient light level) and/or by intrinsic signals such as those of the circadian (24-h) clock in the retina. This review article describes and discusses the extrinsic and intrinsic modulatory processes that enable neural circuits in the retina to optimize their visual performance throughout day and night as the ambient light level changes by ~10 billion-fold. In the first synaptic layer of the retina, cone photoreceptor cells form gap junctions with rods and signal cone-bipolar and horizontal cells (HCs). Distinct extrinsic and intrinsic modulatory processes in this synaptic layer are mediated by long-range feedback of the neuromodulator dopamine. Dopamine is released by dopaminergic cells, interneurons whose cell bodies are located in the second synaptic layer of the retina. Distinct actions of dopamine modulate chemical and electrical synapses in day and night. The retinal circadian clock increases dopamine release in the day compared to night, activating high-affinity dopamine D4 receptors on cones. This clock effect controls electrical synapses between rods and cones so that rod-cone electrical coupling is minimal in the day and robust at night. The increase in rod-cone coupling at night improves the signal-to-noise ratio and the reliability of very dim multi-photon light responses, thereby enhancing detection of large dim objects on moonless nights.Conversely, maintained (30 min) bright illumination in the day compared to maintained darkness releases sufficient dopamine to activate low-affinity dopamine D1 receptors on cone-bipolar cell dendrites. This non-circadian light/dark adaptive process regulates the function of GABAA receptors on ON-cone-bipolar cell dendrites so that the receptive field (RF) surround of the cells is strong following maintained bright illumination but minimal following maintained darkness. The increase in surround strength in the day following maintained bright illumination enhances the detection of edges and fine spatial details.

Interactions of cone cannabinoid CB1 and dopamine D4 receptors increase day/night difference in rod‐cone gap junction coupling in goldfish retina

“…Goldfish were chosen for this study for the following reasons: (1) goldfish cones are relatively large in size compared to those in the retinas of other species (Stell & Harosi, 1976), including mammals, facilitating the study of these cells with electrophysiological recording techniques; (2) in a variety of species including goldfish, mice and rabbits, rod-cone coupling has been observed to be stronger at night than in the day due to control of cone D 4 R activation by the circadian clock in the retina (Ribelayga et al 2008;Besharse & McMahon, 2016;Goel & Mangel, 2021); (3) photoreceptor cells in goldfish and mice express both D 4 Rs and CB 1 Rs (Straiker et al 1999;Yazulla et al 2000;Witkovsky, 2004;Yazulla, 2008;Bouchard et al 2016); and (4) although circadian clock control of rod-cone coupling is conserved among vertebrates, the day/night difference in goldfish is greatest, facilitating the determination of whether there are interactions between CB 1 Rs and D 4 Rs.…”

“…Conversely, the clock increases dopamine release and D 4 R activation in the day, thereby decreasing cAMP, which closes the gap junctions (Fig. 1B) (Wang & Mangel, 1996;Mangel, 2001;Ribelayga et al 2002Ribelayga et al , 2004Ribelayga et al , 2008Goel & Mangel, 2021). Interestingly, although the circadian clock in the goldfish retina increases dopamine release by 3-fold in the day compared to the night (Ribelayga et al 2004;Iuvone et al 2005;Besharse & McMahon, 2016;Ko, 2018;Goel & Mangel, 2021), the day/night difference in rod-cone tracer coupling is remarkably large (∼600-fold greater at night than in the day).…”

“…Studies of goldfish, rabbit and mouse retinas have demonstrated that the circadian (24-h) clock in the retina uses D 4 Rs to modulate the conductance of rod-cone gap junctions (Fig. 1B; Ribelayga et al 2002Ribelayga et al , 2004Ribelayga et al , 2008Goel & Mangel, 2021). The retinal clock lowers dopamine release at night so that D 4 Rs are not activated (Ribelayga et al 2002(Ribelayga et al , 2008Goel & Mangel, 2021).…”

“…1B; Ribelayga et al 2002Ribelayga et al , 2004Ribelayga et al , 2008Goel & Mangel, 2021). The retinal clock lowers dopamine release at night so that D 4 Rs are not activated (Ribelayga et al 2002(Ribelayga et al , 2008Goel & Mangel, 2021). This increases intracellular cAMP, which opens rod-cone gap junctions.…”

“…1B) (Wang & Mangel, 1996;Mangel, 2001;Ribelayga et al 2002Ribelayga et al , 2004Ribelayga et al , 2008Goel & Mangel, 2021). Interestingly, although the circadian clock in the goldfish retina increases dopamine release by 3-fold in the day compared to the night (Ribelayga et al 2004;Iuvone et al 2005;Besharse & McMahon, 2016;Ko, 2018;Goel & Mangel, 2021), the day/night difference in rod-cone tracer coupling is remarkably large (∼600-fold greater at night than in the day). Injecting Neurobiotin, a membrane-impermeable tracer molecule that can diffuse through open, but not closed gap junctions, into a single cone in the dark-adapted intact goldfish retina results in its diffusion into an average of two nearby rods in the day, but into an average of 1200 rods at night (Ribelayga et al 2008;Goel & Mangel, 2021).…”