“Knocking out” a Neural Circuit

Although the visual system occupies nearly half of the mammalian brain, we still do not completely understand its first synaptic stage. One reason is that the dendrites postsynaptic to photoreceptors comprise such a maze of fine processes that doubt remains whether all the second order circuits have been identified—even after 4 decades of electron microscopy. Now advanced functional methods applied to a mammalian rod pathway suggest a circuit previously unsuspected from anatomy.The standard model for two rod circuits is shown in the diagram. The rod terminal contacts a single type of dedicated bipolar cell (left) and also forms an electrical junction with the cone terminal. The rod-to-bipolar circuit is thought to serve starlight, which is so dim that over minutes no rod transduces more than one photon. This single-photon signal requires huge amplification, which renders the circuit vulnerable to saturation in brighter light. The rod-to-cone circuit is thought to serve twilight, which is bright enough that over one second a rod tranduces tens to hundreds of photons. This multi-photon signal can thus “piggyback” onto the cone bipolar circuit (Smith et al. 1986xSmith, R.G., Freed, M.A., and Sterling, P. J. Neurosci. 1986; 6: 3505–3517PubMedSee all ReferencesSmith et al. 1986).NowSoucy and colleagues 1998xSoucy, E., Wang, Y., Nirenberg, S., Nathans, J., and Meister, M. Neuron. 1998; 21: 481–493Abstract | Full Text | Full Text PDF | PubMed | Scopus (161)See all ReferencesSoucy and colleagues 1998 in the September issue of Neuron have used diphtheria toxin controlled by a cone-selective promoter to produce a coneless mouse. The retina, except for the absence of cones and cone-driven responses, looks essentially normal. Bipolar cells that normally collect from cones remain intact, which is somewhat surprising, because neurons commonly degenerate when deprived of their primary input. But most surprising is that the multi-photon rod signal still reaches ganglion cells. Since this signal cannot take the expected route, from rod via gap junctions to cone, the rod must excite an unknown type of bipolar cell.The simplest experiment conceptually would have been to monitor the output of many bipolar cells, one at a time, by intracellular recording. This is technically difficult and extremely tedious. But bipolar cells excite ganglion cells, many of whose individual spike trains can be recorded simultaneously in a multi-electrode dish (Meister et al. 1994xMeister, M., Pine, J., and Baylor, D.A. J. Neurosci. Methods. 1994; 51: 95–106CrossRef | PubMed | Scopus (226)See all ReferencesMeister et al. 1994). So, the experiment actually monitored ganglion cells and blocked the single-photon circuit through the rod bipolar cell with the agonist APB, which also blocks ON cone bipolar cells (7xSlaughter, M.M. and Miller, R.F. Science. 1981; 211: 182–184CrossRef | PubMedSee all References, 3xMuller, F., Wassle, H., and Voigt, T. J. Neurophysiol. 1988; 59: 1657–1672PubMedSee all References). With these circuits blocked, the multi-photon rod stimulus excited OFF ganglion cells. In a coneless retina, this implies a synapse from rod to OFF cone bipolar cells (see figure, indicated in red).In a normal retina, similarly blocked, the multi-photon rod response was also present in OFF ganglion cells. In this case, the electrical pathway could not be ruled out. However, the responses in coneless and normal were virtually identical in amplitude and time course, which would be surprising if their circuits differed. This functional evidence that a normal mouse retina transmits a multi-photon rod signal via an OFF bipolar cell will certainly trigger a search for the anatomical substrate. The diagram suggests a cone bipolar cell that also collects from rods, as reported briefly for gray squirrel (West 1978xWest, R.W. Vision Res. 1978; 18: 129–136CrossRef | PubMed | Scopus (18)See all ReferencesWest 1978). Such a connection might explain how a human “achromat,” born essentially coneless, nevertheless possesses a functional multi-photon rod pathway (Stockman et al. 1995xStockman, A., Sharpe, L.T., Ruther, K., and Nordby, K. Vis. Neurosci. 1995; 12: 951–970CrossRef | PubMedSee all ReferencesStockman et al. 1995).The present results do not contradict the standard version of the “twilight circuit” that routes the multi-photon rod signal via an electrical synapse to the cone. This signal, identified by its rod action spectrum and time course, is recorded in cat and monkey directly from cones (4xNelson, R. J. Comp. Neurol. 1977; 172: 109–136CrossRef | PubMedSee all References, 6xSchneeweis, D.M. and Schnapf, J.L. Science. 1995; 268: 1053–1056CrossRef | PubMedSee all References). Furthermore, since 20 rods couple to each cone, this twilight signal would represent thousands of photons, comparable to what the cone itself supplies in daylight (Smith et al. 1986xSmith, R.G., Freed, M.A., and Sterling, P. J. Neurosci. 1986; 6: 3505–3517PubMedSee all ReferencesSmith et al. 1986). Finally, where a synaptic terminal transmits a multi-photon response via a chemical synapse, it tends first to average the signal by coupling to neighbors (Sterling 1998xSee all ReferencesSterling 1998). This coupling is true for cones in mammals, but in cat and primate it is not the case for rods (5xRaviola, E. and Gilula, N.B. Proc. Natl. Acad. Sci. USA. 1973; 70: 1677–1681CrossRef | PubMedSee all References, 1xKolb, H. J. Neurocytol. 1977; 6: 131–153CrossRef | PubMedSee all References, 8xSmith, R.G., Freed, M.A., and Sterling, P. J. Neurosci. 1986; 6: 3505–3517PubMedSee all References). Thus, if rods in normal mouse do transmit a multi-photon signal to the OFF bipolar cell, they should also form gap junctions with other rods.Figure 1Two Rod Pathways to Ganglion CellsView Large Image | View Hi-Res Image | Download PowerPoint Slide