Mapping physiological inputs from multiple photoreceptor systems to dopaminergic amacrine cells in the mouse retina

Abstract

In the vertebrate retina, dopamine is synthesized and released by a specialized type of amacrine cell, the dopaminergic amacrine cell (DAC). DAC activity is stimulated by rods, cones, and melanopsin-expressing intrinsically photosensitive retinal ganglion cells upon illumination. However, the relative contributions of these three photoreceptor systems to the DAC light-induced response are unknown. Here we found that rods excite dark-adapted DACs across a wide range of stimulation intensities, primarily through connexin-36-dependent rod pathways. Similar rod-driven responses were observed in both ventral and dorsal DACs. We further found that in the dorsal retina, M-cones and melanopsin contribute to dark-adapted DAC responses with a similar threshold intensity. In the ventral retina, however, the threshold intensity for M-cone-driven responses was two log units greater than that observed in dorsal DACs, and melanopsin-driven responses were almost undetectable. We also examined the DAC response to prolonged adapting light and found such responses to be mediated by rods under dim lighting conditions, rods/M-cones/melanopsin under intermediate lighting conditions, and cones and melanopsin under bright lighting conditions. Our results elucidate the relative contributions of the three photoreceptor systems to DACs under different lighting conditions, furthering our understanding of the role these cells play in the visual system.

Orexin-A Suppresses Signal Transmission to Dopaminergic Amacrine Cells From Outer and Inner Retinal Photoreceptors

“…To date, DACs are the only known retinal neurons that receive glutamatergic inputs simultaneously from outer retinal photoreceptors (rods and cones) and inner retinal photoreceptors (ipRGCs). 14 – 19 , 21 – 23 Our results reveal that orexin-A significantly inhibited all DACs that exhibited melanopsin-based light responses. This inhibition was completely blocked by a nonspecific orexin receptor antagonist, suggesting that orexin-A mediates its effects by acting on orexin receptors.…”

“…Rods signal to DACs through the primary rod pathway (rod → rod bipolar cell → AII amacrine → cone bipolar cell → DAC), the secondary rod pathway (rod → cone → cone bipolar cell → DAC), and the tertiary pathway (rod → cone bipolar cell → DAC). 15 , 16 In addition, cones can excite DACs through ON cone bipolar cells directly or indirectly via ipRGCs. 14 , 17 – 20 Cones can also produce ON and OFF inhibitory responses on DACs through distinct OFF bipolar cells and inhibitory amacrine cells.…”

“…DACs receive glutamatergic synaptic input from bipolar cells, which are driven by outer retinal photoreceptors (rods and cones). 14 – 20 In addition, a growing body of evidence has demonstrated that DACs also receive glutamatergic synaptic input from inner retinal photoreceptors, 15 , 16 , 21 – 24 a small population of ganglion cells that respond directly to light via the photopigment melanopsin ( Opn4 ). 25 , 26 These intrinsically photosensitive retinal ganglion cells (ipRGCs) are classified into five subtypes (M1–M5).…”

Functional characterisation of naturally occurring mutations in human melanopsin

“…Recent evidence has revealed additional roles for melanopsin within the classical visual system [ 16 – 20 ], with melanopsin-driven light responses contributing to brightness discrimination [ 91 , 92 ], contrast sensitivity [ 17 , 18 ], and adaptation of visual responses [ 93 , 94 ], via both retrograde signalling within the retina and modulation of dopamine signalling pathways [ 19 , 95 – 99 ], as well as through direct projections of ipRGCs to visual centres [ 16 , 17 ]. Furthermore, people with abnormal melanopsin function could exhibit other symptoms related to the role of melanopsin during postnatal development, including the patterning of retina vasculature [ 100 ], and the refinement and segregation of retinogeniculate projections to visual areas of the brain [ 20 , 21 ], potentially influencing visual acuity in adulthood [ 21 ].…”

NMDA Receptors Contribute to Retrograde Synaptic Transmission from Ganglion Cell Photoreceptors to Dopaminergic Amacrine Cells

“…Before leaving the retina, however, the primary axons of some, if not all ipRGCs, bifurcate and form axon collaterals projecting back toward the outer retina (Joo et al, 2013 ). These collaterals likely make excitatory synapses with a subclass of amacrine cells, dopaminergic amacrine cells (DACs), forming a retrograde signaling pathway within the retina (Zhang et al, 2008 , 2012 ; Atkinson et al, 2013 ; Dkhissi-Benyahya et al, 2013 ; Newkirk et al, 2013 ; Prigge et al, 2016 ; Zhao et al, 2017 ). Given that dopamine acts on almost all retinal neurons, reconfiguring retinal electrical and chemical synapses (Lasater, 1987 ; McMahon et al, 1989 ; Knapp et al, 1990 ; Mills et al, 2007 ), ipRGCs likely influence rod and cone pattern vision via the dopaminergic system (Allen et al, 2014 ; Prigge et al, 2016 ).…”