A New Labor Agreement for the Retina

The retina occupies a special place in neuroscience. It is, after all, still the only part of the vertebrate brain where we can reasonably claim to know what it is for and how it does its job. In fact, this year is just about the thirtieth anniversary of the work of Werblin and Dowling 1969xWerblin, F.S. and Dowling, J.E. J. Neurophysiol. 1969; 32: 339–355PubMedSee all ReferencesWerblin and Dowling 1969 and Kaneko 1970xKaneko, A. J. Physiol. Lond. 1970; 207: 623–633See all ReferencesKaneko 1970 that gave us our model of how the retina works. The model derives from their surveys of the receptive fields of all the main retinal neuron types, plus a little knowledge about the synaptic connections as well as some plausible guesses. In the model, photoreceptors connect to bipolar cells and bipolar cells connect to ganglion cells in a vertical, straight-through pathway. Two horizontal layers of lateral interneurons modify these signals. In the outer retina, horizontal cells modify the spatial properties of the neural image by influencing the photoreceptor to bipolar step, while in the inner retina amacrine cells modify the temporal properties of the neural image by acting at the bipolar to ganglion cell step. At the level of bipolar cells, the neural image is split into two parallel pathways and remains split in ganglion cells and indeed long after signals leave the retina. One category of bipolar cells, the ON bipolar cells, depolarize to light and the other category, OFF bipolar cells, depolarize to darkness. The two categories of bipolar cells have their own halves of the inner synaptic layer. OFF bipolars contact OFF ganglion cells in the upper half, sublamina a, and ON bipolar cells contact ON ganglion cells in the lower half, sublamina b (Famiglietti and Kolb 1976xFamiglietti, E.V. and Kolb, H. Science. 1976; 194: 193–195Crossref | PubMedSee all ReferencesFamiglietti and Kolb 1976). This standard model of the retina is appealingly elegant with its symmetry and division of labor. Regrettably though, evolution is an inveterate tinkerer with no regard for simplicity, symmetry, or elegance, and so perhaps it is not surprising that discoveries of exceptions to the beautiful plan were not long in coming.One of the quirkiest exceptions is in the mammalian retina where rod photoreceptors have their own special bipolar cell, yet these bipolars don't make direct contact with any ganglion cells. Instead, they synapse onto a particular amacrine cell, the AII amacrine, which makes a glycinergic synapse onto cone OFF bipolars and is electrically coupled to cone ON bipolar cells, which do make contact with ganglion cells. These are not the only routes by which rod signals reach ganglion cells. We have known for a long time that some rod signals leak into cones via electrical junctions (Nelson 1977xNelson, R. J. Comp. Neurol. 1977; 172: 109–135Crossref | PubMedSee all ReferencesNelson 1977), but this is not the whole story either. Using transgenic mice without any conesSoucy et al. 1998xSoucy, E., Wang, Y., Nirenberg, S., Nathans, J., and Meister, M. Neuron. 1998; 21: 481–493Abstract | Full Text | Full Text PDF | PubMed | Scopus (189)See all ReferencesSoucy et al. 1998 showed that when transmission to the rod bipolar is blocked, rod signals nevertheless still got through to ganglion cells. Careful EM reconstructions, by Peichl's group, of the rodent retina, immunogold labeled for AMPA receptor subunits, shows that the novel pathway probably involves a rare synapse from rods to cone OFF bipolars (Hack et al. 1999xHack, I., Peichl, L., and Brandstatter, J.H. Proc. Natl. Acad. Sci. USA. 1999; 96: 14130–14135Crossref | PubMed | Scopus (122)See all ReferencesHack et al. 1999).In this issue of Neuron, DeVries further erodes the standard model, this time with respect to the location in which separate temporal channels are set up (DeVries 2000xDeVries, S.H. Neuron. 2000; 28: 847–856Abstract | Full Text | Full Text PDF | PubMed | Scopus (247)See all ReferencesDeVries 2000). In the standard model this, of course, is the inner retina. DeVries uses the ground squirrel retina, which has almost all cone photoreceptors, like our own fovea. Each cone photoreceptor makes synaptic contact with six types of bipolar cell, three of which are ON cells and three of which are of the OFF type. The ON bipolar cells depolarize when photoreceptors hyperpolarize in response to light, and to achieve this sign inversion, they employ a metabotropic receptor for the cone transmitter, glutamate. OFF bipolars are simpler, using common ionotropic AMPA/KA receptors. So how are the three kinds of OFF bipolar cells different from each other? What DeVries shows is that on careful examination, the three types, which he shows are anatomically recognizable when filled with dye from the patch pipet (see DeVries, Figure 1), each have characteristic receptors. Two of them are KA preferring and one is an AMPA receptor. To examine the kinetics of these receptors, DeVries uses the pipet to gently lift the cell body and dendrites of a bipolar cell from a slice into a flowing stream that allows rapid solution changes. The b2 bipolar cell, the one with AMPA receptors, recovers quickly from desensitization following the application of glutamate, but the b3 bipolar, with a KA receptor, takes more than 1 s for full recovery. The b7 bipolar cell has a different kind of KA receptor and it has intermediate kinetics. By simultaneously voltage-clamping a cone and a connected bipolar cell, DeVries shows that the recovery of the AMPA receptor from desensitization is not a rate-limiting step in the transmission from cone to b2 bipolar cell. Instead, some presynaptic step, like replenishing the supply of synaptic vesicles in the cone terminal, is limiting. In the case of the b3 bipolar cell, though, the KA receptor determines the dynamics of recovery. To drive home the point that a cone's signal has different temporal representations in different bipolar cells, DeVries, in a tour de force, records simultaneously from a b2 and a b3 bipolar cell while driving both of them with the same cone.In the life of a ground squirrel, cone cells don't experience constant saturating intensities of light interspersed with the occasional flash of darkness, the equivalent of the voltage regime applied to cones in the DeVries study. Mostly, their membrane potentials jog around in the middle of their voltage range. What effect will receptor kinetics have under these circumstances? A quantitative answer will have to wait for a more sophisticated experiment, but the gist is already clear. b3 cells will show sustained responses, and the b2 cells will be transient. Very probably the transient b2 cells will make contact with the transient Y type ganglion cells, and the b3 cells will drive the slow X type ganglion cells. For the ground squirrel retina, this is a plausible suggestion only since the properties of the ganglion cells are not known, but a recent study by Awatramani and Slaughter 2000xAwatramani, G.B. and Slaughter, M.M. J. Neurosci. 2000; 20: 7087–7095PubMedSee all ReferencesAwatramani and Slaughter 2000 lends support to this idea. Here they show that in the salamander retina, some morphological classes of ON bipolar cells are transient, while others have sustained responses to light. Again, this is due to the properties of the receptor for the photoreceptor transmitter, but the point here is that, as you would suppose, sustained bipolars drive sustained ganglion cells, whereas transient bipolars drive transient ganglion cells.If parallel temporal pathways are set up in the outer retina, does this mean that the inner retina is not involved? The evidence (for example8xNirenberg, S. and Meister, M. Neuron. 1997; 18: 637–650Abstract | Full Text | Full Text PDF | PubMedSee all References, 3xDong, C.J. and Werblin, F.S. J. Neurophysiol. 1998; 79: 2171–2180PubMedSee all References) argues that, on the contrary, amacrine cells contribute plenty of temporal tweaking. Like the case of the passage of rod signals to ganglion cells in mammals, we can expect that multiple mechanisms will be contributing.So the division of labor is not as clean as we thought. Parallel temporal pathways are established in the outer retina after all, and once again, the facts spoil a beautiful picture. But perhaps there could be a silver lining to this cloud. It may yet turn out, in a reprise of the discovery that ON and OFF pathways have their own sublaminae in the inner synaptic layer, that the different temporal inputs to the inner synaptic layer are layered in some intelligible pattern.