“Knocking out” a Neural Circuit
Authors: Peter Sterling
Journal: Neuron (1998)

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 (8Smith R.G. Freed M.A. Sterling P. J. Neurosci. 1986; 6: 3505-3517PubMed Google Scholar). Now9Soucy E. Wang Y. Nirenberg S. Nathans J. Meister M. Neuron. 1998; 21: 481-493Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar 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 (2Meister M. Pine J. Baylor D.A. J. Neurosci. Methods. 1994; 51: 95-106Crossref PubMed Scopus (316) Google Scholar). 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 (7Slaughter M.M. Miller R.F. Science. 1981; 211: 182-184Crossref PubMed Scopus (658) Google Scholar, 3Müller F. Wässle H. Voigt T. J. Neurophysiol. 1988; 59: 1657-1672PubMed Google Scholar). 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 (12West R.W. Vision Res. 1978; 18: 129-136Crossref PubMed Scopus (41) Google Scholar). Such a connection might explain how a human “achromat,” born essentially coneless, nevertheless possesses a functional multi-photon rod pathway (11Stockman A. Sharpe L.T. Rüther K. Nordby K. Vis. Neurosci. 1995; 12: 951-970Crossref PubMed Scopus (43) Google Scholar). 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 (4Nelson R. J. Comp. Neurol. 1977; 172: 109-136Crossref PubMed Scopus (248) Google Scholar, 6Schneeweis D.M. Schnapf J.L. Science. 1995; 268: 1053-1056Crossref PubMed Scopus (236) Google Scholar). 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 (8Smith R.G. Freed M.A. Sterling P. J. Neurosci. 1986; 6: 3505-3517PubMed Google Scholar). 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 (10Sterling, P. (1998). In The Synaptic Organization of the Brain, Fourth Edition, G.M. Shepherd, ed. (New York: Oxford University Press), pp. 205–253.Google Scholar). This coupling is true for cones in mammals, but in cat and primate it is not the case for rods (5Raviola E. Gilula N.B. Proc. Natl. Acad. Sci. USA. 1973; 70: 1677-1681Crossref PubMed Scopus (261) Google Scholar, 1Kolb H. J. Neurocytol. 1977; 6: 131-153Crossref PubMed Scopus (179) Google Scholar, 8Smith R.G. Freed M.A. Sterling P. J. Neurosci. 1986; 6: 3505-3517PubMed Google Scholar). 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.