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To record from a cell in the nervous system is one thing: it is another to record from a cell and know exactly what kind of cell it is. This microscopic picture shows a single bipolar cell in the retina of a goldfish, recorded in 1971 by Akimichi Kaneko, then at Harvard Medical School.
The fact that it is a bipolar cell and not an amacrine or horizontal cell was proven by injecting a fluorescent dye, procyon yellow, through the microelectrode. The dye spread throughout the cell, revealing its shape. In this cross section, receptors are on top.




                        BIPOLAR CELLS AND                              HORIZONTAL CELLS
Horizontal cells and bipolar cells occur, along with amacrine cells, in the middle layer of the retina. The bipolar cells occupy a strategic position in the retina, since all the signals originating in the receptors and arriving at the ganglion cells must pass through them. This means that they are a part of both the direct and indirect paths. In contrast, horizontal cells are a part of the indirect path only. As you can see from the diagram on page 38, horizontal cells are much less numerous than bipolar cells, which tend to dominate the middle layer.
Before anyone had recorded from bipolar cells, the big unknown was whether they would prove to have center-surround receptive fields, as ganglion cells do, and come in two types, on center and off center. If the answer was yes, it would almost certainly mean that the organization discovered by Kuffler for ganglion cells was a passive reflection of bipolar-cell organization.
The knowledge that the receptive fields of bipolar cells were indeed centersurround and were of two types came from intracellular recordings first made by John Dowling and Frank Werblin at Harvard Biological Laboratories and by Akimichi Kaneko at Harvard Medical School. The next question is how these receptive fields are built up. To answer it we have to begin by examining the connections of receptors, bipolar cells, and horizontal cells.
The bipolar cell sends a single dendrite in the direction of the receptors. This either synapses with one receptor (always a cone) or it splits into branches that synapse with more than one receptor. When more than one receptor feeds into a single bipolar cell, they collectively occupy a relatively small area of retina. In either case, these receptors must account for the receptive-field center, because the area they occupy matches the field center in size. The next question is whether the synapses between receptors and bipolar cells are excitatory or inhibitory, or both.
Bipolar cells, like receptors and horizontal cells, do not fire impulses, but we still speak of an on response, meaning a depolarization to light and therefore increased transmitter release from the cell's terminals, and an off response, to imply hyperpolarization and decreased release. For the off-center bipolars the synapses from the receptors must be excitatory, because the receptors themselves are turned off (hyperpolarized) by light; for the on-center bipolars the synapses must be inhibitory. To see why (if you, like me, find this confusing), you need only think about the effects of a small spot of light. Receptors are active in the dark: light hyperpolarizes them, turning them off. If the synapse is excitatory, the bipolar will have been activated in the dark, and will likewise be turned off by the stimulus. If the synapse is inhibitory, the bipolar will have been suppressed in the dark, and the light, by turning off the receptor, will relieve the suppression of the bipolar cell—that is, the bipolar cell will be activated. (No one said this would be easy.)
Whether the receptor-to-bipolar synapse is excitatory or inhibitory could depend on either the transmitter the receptor releases or the nature of the channels in the bipolar cell's postsynaptic membrane. At present no one thinks that one receptor releases two transmitters, and much evidence favors the idea that the two biolar types have different receptor molecules.
Before we discuss where the receptive-field surrounds of the bipolar cells come from, we have to consider the horizontal cells.
Horizontal cells are important because they are probably at least in part responsible for the receptive-field surrounds of retinal ganglion cells; they represent the part of the indirect pathway about which we know the most. They are large cells, and among the strangest in the nervous system. Their processes make close contact with the terminals of many photoreceptors distributed over an area that is wide compared with the area directly feeding a single bipolar cell. Every receptor contacts both types of second-order cell, bipolar and horizontal.
Horizontal cells come in several subtypes and can differ greatly from species to species; their most unusual feature, which they share with amacrine cells, is their lack of anything that looks like an ordinary axon. From the slightly simplified account of nerve cells given in the last chapter you may rightly wonder how a nerve without an axon could transmit information to other neurons. When the electron microscope began to be used in neuroanatomy, we soon realized that dendrites can, in some cases, be presynaptic, making synapses onto other neurons, usually onto their dendrites. (For that matter, axon terminals can sometimes be postsynaptic, with other axons ending on them.) The processes that come off the cell bodies of horizontal cells and amacrine cells apparently serve the functions of both axons and dendrites.

 

 

 

 

 

 

 

 

 

The synapses that horizontal cells make with receptors are likewise unusual, lacking the electron-microscopic features that would normally tell us which way the information is conveyed. It is clear that receptors feed information to horizontal cells through excitatory synapses because horizontal cells, like receptors, are in most cases hyperpolarized, or turned off, by light. It is less clear where the horizontal cell sends its output: in some species such as turtles we know that they feed information back to receptors; in other species they make synapses with the dendrites of bipolar cells and doubtless feed into them; in primates we do not have either type of information. In summary, horizontal cells get their input from receptors; their output is still uncertain, but is either back to receptors, or to bipolar cells, or to both.
The relatively wide retinal area over which receptors supply horizontal cells suggests that the receptive fields of horizontal cells should be large, and they are. They are about the size of the entire receptive fields of bipolar cells or ganglion cells, center plus surround. They are uniform, giving hyperpolarization wherever you stimulate, and more hyperpolarization the larger the spot.
Much evidence points to the horizontal cells as being responsible for the receptive-field surrounds of the bipolar cells—indeed they are the only plausible candidates, being the only cells that connect to receptors over so wide an expanse. When horizontal cells connect directly to bipolars, the synapses to on-bipolars would have to be excitatory (for the effect of light in the surround to be inhibitory) and those to off-bipolars, inhibitory. If the influence is by way of the receptors, the synapses would have to be inhibitory.
To sum this up: Bipolar cells have center-surround receptive fields. The center is supplied by direct input from a small group of receptors; the surround arises from an indirect path stemming from a wider expanse of receptors that feed into horizontal cells, which probably feed into the bipolars. The indirect path could also be the result of the horizontal cells feeding back and inhibiting the receptors.

   
 
 
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A hypothetical circuit shows how centersurround receptive fields are thought to be built up. The receptive field center of a bipolar cell (fourth purple cell from top), an off center cell in this example, is produced by a small patch of receptors, making powerful excitatory synaptic contacts.
One or several such cells feed into a ganglion cell to form its center. The surround of the bipolar cell's receptive field is produced by a much larger number of receptors (including those in the central patch), which feed a horizontal cell with excitatory synapses. The horizontal cell may contact the bipolar cell or project back onto the receptors.
If the bipolar cell is off center, the synapses onto the bipolar cell from the central patch of receptors are presumed to be excitatory. (The receptors are turned off by light.) The horizontal cell is presumed to inhibit either the bipolar cell or the receptors themselves. Note two input paths to ganglion cells, one directly from bipolars and the other from bipolar to amacrine to ganglion cell.