The involvement of glutamate-gated channels in negative feedback from horizontal cells to cones.

Photoreceptors are the light sensitive cells in the retina. They project to horizontal cells and bipolar cells via a glutamatergic feed forward pathway. Horizontal cells are strongly electrically coupled and integrate in that way the input from the photoreceptors. Horizontal cells feedback to cones negatively. The combined signal from the photoreceptors and the horizontal cells is sent to the bipolar cells. The feedback pathway from horizontal cells to cones is thought to form the basis for the center/surround organization of bipolar cells. The nature of the feedback pathway is an issue of intense debate. It was thought for a long time that this feedback pathway was GABAergic, because cones have GABA-receptors and horizontal cells release GABA via a GABA-transporter working in the reversed direction. However, recently we showed in goldfish that horizontal cells feed back to cones via an alternative mechanism. In goldfish, negative feedback from horizontal cells to cones shifts the calcium current of the cone to more negative potentials. This feedback pathway is independent of GABA, since feedback cannot be blocked by either saturating concentrations of PTX, the GABA-transporter blocker SKF89976A, or application of GABA. The mechanism of negative feedback from horizontal cells to cones involves hemichannels located at the tips of the invaginating horizontal cells, just opposite to the calcium channels of the cones. Current flowing through these hemichannels changes the extracellular potential deep in the synaptic cleft and in that way modulates the calcium current of the cones. Such a modulation of the extracellular potential is called ephaptic. If negative feedback from horizontal cells to cones is indeed ephaptic, other channels present in the synapse should also be able to act as a current source, i.e., should also be able to change the output of the cone. We showed that glutamate-gated channels present at the tips of the horizontal cell dendrites can also mediate feedback responses. Surprisingly, although the glutamate-gated conductance of the horizontal cells is eight times the hemichannel conductance, glutamate-gated channels are not the major current source in negative feedback from horizontal cells to cones. In this chapter we present evidence that this is due to the more focal localization of the hemichannels, compared to a diffuse and extrasynaptic localization of the glutamate-gated channels.