How do horizontal cells 'talk' to cone photoreceptors? Different levels of complexity at the cone-horizontal cell synapse

Abstract

The first synapse of the retina plays a fundamental role in the visual system. Due to its importance, it is critical that it encodes information from the outside world with the greatest accuracy and precision possible. Cone photoreceptor axon terminals contain many individual synaptic sites, each represented by a presynaptic structure called a 'ribbon'. These synapses are both highly sophisticated and conserved. Each ribbon relays the light signal to one ON cone bipolar cell and several OFF cone bipolar cells, while two dendritic processes from a GABAergic interneuron, the horizontal cell, modulate the cone output via parallel feedback mechanisms. The presence of these three partners within a single synapse has raised numerous questions, and its anatomical and functional complexity is still only partially understood. However, the understanding of this synapse has recently evolved, as a consequence of progress in understanding dendritic signal processing and its role in facilitating global versus local signalling. Indeed, for the downstream retinal network, dendritic processing in horizontal cells may be essential, as they must support important functional operations such as contrast enhancement, which requires spatial averaging of the photoreceptor array, while at the same time preserving accurate spatial information. Here, we review recent progress made towards a better understanding of the cone synapse, with an emphasis on horizontal cell function, and discuss why such complexity might be necessary for early visual processing.

Keywords: GABA; global feedback; horizontal cell; local circuit; outer retina; photoreceptor; presynaptic inhibition; synaptic microdomain.

Figure 1. Organization of the mouse retina and the cone photoreceptor synapse

A, schematic representation of a vertical section of the mouse retina, consisting of five neuronal classes organized in different layers. AC, amacrine cell; BC, bipolar cell; C, cone photoreceptor; GC, ganglion cell; GCL, ganglion cell layer; HC, horizontal cell; INL, inner nuclear layer; IPL, inner plexiform layer; ONL, outer nuclear layer; OPL, outer plexiform layer; R, rod photoreceptor. B, volume‐rendered individual HC (red) and contacting cone axon terminals (purple); HC traced by Yue Zhang using a published EM dataset (Helmstaedter et al. 2013); 3D volume rendering by Christian Behrens. C, schematic organization of the cone synapse: Simplified cone axon terminal (purple) with a single exemplary ribbon (black vertical line) surrounded by numerous synaptic vesicles (white), with two invaginated lateral HC dendritic processes (red) and an ON cone BC dendrite (dark grey). OFF cone BC dendrites (light grey) are located at the base of the cone axon terminal. Note that an individual mouse cone axon terminal contains ∼10 ribbon synapses. Scale bar: 10 μm.

Figure 2. Global and local signal processing at the cone‐to‐horizontal cell synapse

A, schematic representation of global feedback in an individual HC or in the electrically coupled HC network. Cones (purple) release glutamate (black arrows) which is received by HCs (red) that in turn provide global feedback to cones (grey arrows) due to spread of signals in the HC network via gap‐junctions (black zigzag). B, schematic representation of local (cone synapse‐specific) HC feedback. HC dendritic processes may feed back onto individual cones independently from neighbouring dendritic processes (grey/black double arrows). C, hypothesized ribbon‐specific presynaptic microdomains at different synaptic clefts in a single cone axon terminal. Two ribbons contacting dendrites of two different types of ON cone BC (dark and light green) differ in glutamate release rate (black circles) and synaptic strength (arrows). BC, bipolar cell. D, overview of the connectivity between cones and two neighbouring HCs (orange and red). HC, horizontal cell. The black box corresponds to the enlarged schemata shown in E and F. E and F, two alternative hypotheses for the processing of cone signals in HC distal dendrites (postsynaptic microdomains). E, two electrically coupled processes from two distinct HCs (orange and red) act as a single input–output structure (double arrow) due to their gap‐junctional communication (black symbol). F, the two lateral HC processes may be independent of each other and act as individual ‘post‐synaptic microdomains’ (grey and black arrows). Note that only two ribbon synapses are shown for the mouse cone axon terminal in C, E and F instead of ∼10 ribbon synapses per cone.

Figure 3. Speculative chromatic horizontal cell feedback in primate and mouse retinae

A, schematic representation of colour opponency in an S‐cone generated by an HII cell in the primate retina when a green/red light stimulus is presented. M‐/L‐cones (green/red) provide glutamatergic input (thin black arrows indicate weak synaptic contacts) that is summed by the HII (dark grey), which in turn provides lateral feedback to the S‐cone (blue) (thick grey arrow indicates strong feedback). B, scheme showing the speculative colour opponency in S‐cones in the mouse retina generated by an HC when a green light stimulus is given. M‐cones (green) release glutamate (black arrows) that is received and integrated by the HC (light grey), which in turn provides feedback (grey arrows) to S‐cones (blue). C, schematic representation of global feedback generated by a primate HI cell. Only M‐/L‐cones (green/red) but no S‐cones (not shown) provide glutamatergic drive (black arrows) to the HI cell (dark grey) that feeds back to M‐/L‐cones (grey arrows). D, speculative global S‐cone‐specific feedback generated by a primate HII cell. S‐cones (blue) make strong contacts (thick black arrows) with an HII cell (dark grey) whereas M‐/L‐cones (green/red) make weaker contacts (thin black arrow). S‐cone signals are predominantly converted into feedback to S‐cones (blue arrows). E, speculative local feedback to S‐ (blue) and M‐ (green) cones in the mouse retina. Glutamatergic input from cones (black arrows) is not globally processed in mouse HC dendrites (light grey). Instead, feedback is generated locally in distal HC dendritic tips and provided in a cone‐specific way (green and blue arrows).