hyperpolarized; the membrane potential approaches −75 mV. The change in potential is graded, the level of hyperpolarization depends on the amount of light absorbed and the number of visual pigment molecules activated. The magnitude of the hperpolarization determines the change in the amount of transmitter released, either slowing or stopping the flow.78 Once the level of cGMP is restored, the ion channels open and the cell once again becomes depolarized and releases glutamate. The amount of transmitter released by the photoreceptor decreases as the amount of light absorbed increases.

In the rod, the process of phototransduction begins with the absorption of a photon of light that causes the breaking of a double bond in 11-cis-retinal forming the isomer all-trans-retinal. A sequence of conformational changes in rhodopsin results and several intermediaries are formed. Activated metarhodopsin II stimulates transducin, the G-protein of visual transduction, and is then transformed into inactive metarhodopsin III; finally all- trans-retinal dissociates from the photopigment.27 The visual pigment is now said to be bleached. The phototransduction cascade causes the decrease of cGMP, leading to hyperpolarization of the photoreceptor.

All-trans-retinal moves from the disc lumen into the cytoplasm where it is reduced to all-trans-retinol. The photoreceptor cannot re-isomerize the molecule, so it must be transported by specific carrier proteins within the interphotoreceptor matrix (IPM) to the RPE.81 These cells contain the enzymes that convert all-trans-retinol to 11-cis-retinol and finally oxidize it back to11-cis- retinal; 11-cis-retinal is then transported back through the IPM to be incorporated into the photopigment. In the cone recycling process, some animal models indicate that the Müller cell has a role in the visual cycle by taking up all-trans-retinol and re-isomerizing it to 11-­cis-retinol, which is then transported back to the cone and oxidized to 11-cis-retinal and incorporated into the photopigment.102,103 The steps of the rod renewal system are well known, but those of the cone renewal system are still unclear.

Information Processing

Once the photoreceptor is activated and the message begins its circuit through the retinal neurons, organization and processing will take place prior to the signal exiting the eye. Since a million ganglion cells receive input from over a hundred million photoreceptors, there must be a systematic process to control and relay photoreceptor messages. Retinal neurons have been given designations as ON cells or OFF cells as a means to describe the processing schematic.

Retinal neurons are named ON or OFF cells by the light condition when the cell is depolarized. A cell that is depolarized with light OFF is called an OFF cell and

a cell that is depolarized with light ON is called an ON cell. Since all photoreceptors depolarize in the dark, all photoreceptors are OFF cells.

Glutamate will cause a bipolar cell to either depolarize or hyperpolarize depending on the type of receptor present in the plasma membrane of the bipolar dendrite.104,105 Bipolars cells with ionotropic receptors in their membrane respond to glutamate with a depolarization and are OFF bipolars and bipolar cells that have metabotropic receptors in their membrane respond to glutamate with a hyperpolarization and are ON bipolars.104,105 The neurotransmitter at the axon terminal in bipolar cells is also glutamate (Glu) and bipolars release Glu when they are in the depolarized state.

When a photoreceptor is depolarized (thus it is in the dark, light is OFF) it is releasing Glu. When Glu binds to the ionotropic receptor on a bipolar dendrite, cation channels are opened in the cell membrane, causing the bipolar cell to depolarize and release Glu.106 This is an OFF bipolar because it is depolarized in the dark. When Glu binds to the metabotropic receptors on a bipolar cell dendrite, a decrease of cGMP occurs, closing cation channels in the cell membrane and causing the bipolar cell to hyperpolarize, resulting in a decrease of glutamate release.107 This is an ON bipolar because it is hyperpolarized in the dark.

When the photoreceptor is hyperpolarized (light is ON), Glu release is reduced or stopped. The lack of Glu at the ionotropic receptor causes the Glu-gated ­cationic channels in the bipolar membrane to close. The OFF bipolar cell hyperpolarizes, reducing its release of neurotransmitter.106 When Glu is reduced or no longer present, the lack of Glu at the metabotropic receptor signals a cGMP cascade, cGMP increases, cGMP-gated cation channels open, and the ON bipolar depolarizes, which increases its neurotransmitter release.107

Succinctly put: The OFF bipolar depolarizes in dark and hyperpolarizes in light. The ON bipolar depolarizes in light and hyperpolarizes in dark.

Some current literature uses other terms. OFF bipolars are also called hyperpolarizing bipolar cells (HBCs) and ON bipolars are also called depolarizing bipolar cells (DBCs). (This terminology reflects the state of the bipolar when the light is on.) Recognize that the ON or OFF designation does not imply that the bipolar itself is responding to the light condition; only photoreceptors do that.

Generally, the ON bipolar dendrite synapses within a photoreceptor invagination and the OFF bipolar dendrite synapses only with cones and on the flat part of the pedicle. Each cone in central retina contacts both an ON and an OFF midget bipolar.78 All rod bipolars are ON cells (Figure 4-25).

Bipolar axons end in the IPL. One synaptic configuration is a dyad, which consists of a synapse between a

Rod

Cone

FIGURE 4-25

Schematic of ON and OFF bipolar pathways. OFF bipolar dendrite synapses on flat part of cone, ON bipolar dendrite synapses within photoreceptor invagination; OFF bipolar axon terminates in sublamina a, ON bipolar axon terminates in sublamina b; AII amacrine cell relays rod signals to both ON and OFF ganglion cells.

bipolar axon and two post synaptic elements, either two amacrine processes or one amacrine process and one ganglion dendrite. ON and OFF bipolar axons terminate in different tiers of the IPL. OFF bipolars synapse in the outer tier, sublamina a (nearest the INL), and ON bipolars synapse in the inner tier, sublamina b, closest to the ganglion cell layer.78 Rod bipolars do not synapse with ganglion cells directly but with amacrine cells; thus the rod signal must pass through a four neuron chain (see Figure 4-25).

Bipolar cells transfer information to retinal ganglion cells, which are the first cells in the visual pathway to respond with an action potential. Once a threshold is reached, the ganglion cell responds and a signal is sent to higher CNS locations. All other retinal neurons give graded responses, the intensity of which is determined by the intensity of the stimulus.

The P ganglion cells terminate in the parvocellular layers of the LGN, are associated with cone bipolar cells, and carry color information. The P1 cells, also called

mdget ganglion cells are concentrated in central retina, and constitute 80% of the ganglion cell population.78 M ganglion cells project to the magnocellular layers of the LGN. They have also been called parasol ganglion cells because of their large spreading dendritic trees. Because they have such expansive processes and cover a large area of retina, they can respond rapidly to moving or changing stimuli.

The vertical connections through the retina have been described, but horizontal and amacrine cells interconnect in a horizontal direction. They link one region of retina with another allowing a signal sent by a photoreceptor to be influenced by a signal from a photoreceptor in a different retinal location, thus modifying the message.

Horizontal cells communicate with other horizontal cells through gap junctions and receive excitatory input through chemical synapses from photoreceptors. Horizontal cells provide inhibitory feedback to photoreceptors and inhibitory feed forward to bipolars.78

In the dark, while the photoreceptor is continuously releasing the excitatory neurotransmitter glutamate, its horizontal cells are depolarized. With light stimulation the photoreceptor hyperpolarizes and transmitter release is reduced. Ligand-gated channels close in the horizontal cell membrane, causing it to hyperpolarize.108 The amplitude and duration of the response depends on the strength of the photoreceptor hyperpolarization, and thus on the intensity and duration of the light stimulus.92,108 Because horizontal cells are joined by gap junctions a great number of horizontal cells can be affected when just one is influenced by a photoreceptor.

The mechanism by which the inhibitory message is passed from the horizontal cell to the cone is not fully understood. It was once thought that the horizontal cell released the inhibitory neurotransmitter GABA. Subsequent studies have raised doubts that GABA is a major player in the feedback process from horizontal cells.99,109 It is speculated (based on animal models) that a change in the horizontal cell polarization causes a current change in the extracellular potential in the synaptic cleft within an invagination. This could affect the Ca++ channels in the synaptic membrane of the cone influencing the synaptic vesicle release of Glu without actually changing the cone membrane potential. The change in neurotransmitter release would affect the bipolar dendrites within the invagination and in some cases might reverse their reaction.99,108,109

Amacrine cells also carry information in a horizontal direction. There are 40 different types but the circuitry of only a few has been established. Amacrine cells are generally inhibitory and release either GABA or glycine. Amacrine processes make conventional synapses with bipolar axons and with ganglion cell dendrites or soma.

The conventional chemical synapse with bipolar cell axons are feedback synapses; synapses on ganglion cells are feed-forward synapses.110 Amacrine cells also synapse with other amacrine cells.

The narrow-field rod amacrine cell, AII, releases glycine. It is the intermediary between the rod bipolar and the ganglion cell. An AII amacrine cell gathers information from about 300 rods.78 The AII provides connection between the ON and OFF pathways. The AII receives information from a rod bipolar axon (an ON cell) in sublamina b of the IPL, and relays information by a conventional synapse to an OFF cone bipolar in sublamina a, thereby influencing an OFF ganglion cell. The AII also carries rod information to an ON cone bipolar axon through gap junctions in sublamina b and influences an ON ganglion cell.61 AII amacrine cells, whose processes are joined by gap junctions, form a weak electrical syncytium.78

The A17 amacrine cells are wide-field diffusely branching cells. They appear to interconnect rod bipolar cells but do not appear to make synapses with other amacrines nor ganglion cells.110 A single A17 amacrine cell can receive input from as many as 1000 rod ­bipolars.110 They are thought to amplify signals in dim illumination.

The A18 amacrine cell is a wide-field amacrine with an extensive dendritic tree. It seems to have a role in the regulation of scotopic vision flow, and in modulating retinal adaptation to differing light conditions. It can interfere with the AII amacrine synapse with cone bipolar cells, and effectively reduce the size of the receptive field.92 The A18 releases dopamine, which can disrupt the gap junctions that forms the syncytium of AII amacrines. Dopamine released by the A18 amacrine may also have some function in the circadian cycle.111

Interplexiform neurons have processes in both the OPL and the IPL and convey signals between these layers, that is, from inner retina to outer. They might secrete dopamine as their transmitter but further details about their physiology is lacking.112

Receptive Fields

ON and OFF cells provide two information processing channels for differentiating light and dark signals. Flat bipolars are the start of the OFF channel and invaginating bipolars are the start of the ON channel. The ON and OFF channels in the cone pathway begin at the pho- toreceptor-bipolar connection because cones synapse with both ON and OFF bipolar cells. In the rod pathway, because a rod synapses only with an ON bipolar, the competing channels begin with the AII amacrine cell.

Retinal processing can be described in terms of receptive fields. A receptive field consists of the area in the visual field or the area of the retina that, when stimulated, elicits a response in a retinal neuron. The receptive

field for a particular bipolar cell consists of those photoreceptor cells with which it is in direct contact, and all the photoreceptors and horizontal cells that can influence it. Because neighboring horizontal cells are joined by gap junctions, the receptive field is consequently enlarged beyond its dendritic tree.

Retinal receptive fields are arranged in a center-sur- round pattern. When light activates cells in the center of the field, a given response occurs. When light falls on the surround (the annular region immediately around the center), an antagonistic response occurs. The response by the cells in the surround inhibits the response from the cells in the center. This pattern is seen at the level of the bipolar cells, the ganglion cells, and in LGN and the striate cortex. When cells in the surround are activated, the signal coming from the center cell is changed to the opposite response. The center-surround response occurs in part due to lateral inhibition by horizontal cells and because of amacrine cell activity on bipolar axon terminals.113

The center-surround configuration allows a neuron to not only respond to a direct message but to gather information from neighboring areas providing details about the bigger picture that then influences that neuron. This process aides in the detection of edges and in the recognition of contrast, and it maximizes retinal contrast sensitivity through a wide range of background illuminations.78

A circular receptive field can be either ON-center/OFF surround or OFF-center/ON surround. When light falls on the annular region, the message from the center is inhibited: i.e., when an ON-center cell is stimulated, it sends its ON message, but when cells in its surround are also stimulated, the ON-center cell will be inhibited and the ON message is not sent, and instead an OFF message is recognized; the converse occurs if the surround of an OFF-center cell is stimulated the message sent from the center will be an ON message.

Light and Dark Adaptation

The visual system is highly specialized for the detection and analysis of patterns of light; by visual adaptation, it can modify its capacity to respond at extremely high and low levels of illumination. The level of background illumination can affect the both the ease and the speed with which a photoreceptor responds. When a significant change in light level occurs, adaptation can be prolonged; it can take 30 minutes for the retina to adapt fully when going from bright sunlight to complete dark (dark adaptation). At first only cones are functioning, but since they are now in the dark they are not stimulated and the rods take some time to reach maximum function. Light adaptation, going from complete dark to bright light, takes approximately 5 to 10 minutes; the cones reach their functional mode much more