Feedback, both Fast and Slow: How the Retina Deals with Redundancy in Space and Time

By the time visual information leaves the retina for the brain, it has undergone several rounds of processing. Most prominently, that information has been filtered to amplify differences in contrast, between either two points in space or two points in time. The initial step in that amplification is carried out by horizontal cells, whose job is not only to receive signals from a group of adjacent photoreceptor cells (rods or cones) but also to send inhibitory feedback signals back to the photoreceptors, turning down the weakest outputs and allowing only the strongest to get through. This much has been known for several decades, but the cell physiological details of the feedback mechanism have been controversial. Part of the puzzle has been the paradoxical requirement for both very fast feedback, needed to highlight spatial differences, and slower feedback, needed to process temporal ones. In this issue of PLOS Biology, Rozan Vroman, Maarten Kamermans, and colleagues resolve this apparent paradox: they show that horizontal cells in the goldfish retina employ two simultaneous feedback mechanisms, the slower of which relies on a newly described mechanism, creating an extracellular buffer by secreting and hydrolyzing ATP. Horizontal cells affect the activity of cone cells by changing the rate of flow of positively charged calcium ions from the extracellular space through calcium channels into the cone cell. The authors measured that current within individual cone–horizontal cell synapses, and found that the curve reflecting the current change was best described as the sum of two exponential functions, one representing an initial fast increase and the other a slower one. The fast component was very fast indeed, inconsistent with the inevitable delay imposed when cells are separated by a synaptic gap. Instead, the authors show that connexin hemichannels on the horizontal cell membrane were involved. These channels allowed current to flow into the horizontal cell, increasing the negative charge of the intercellular space and increasing the flow of calcium into the cone cell, locally depolarizing it. This direct (‘‘ephaptic’’) connection makes the synapse among the fastest of all known inhibitory synapses. But it was the slow component that held the most surprises. The authors noted that