Lateral Inhibition and Protons: The First Level of Contrast in Stimulation of the Retina?

Lateral inhibition mediated by horizontal cells in the outer plexiform layer of the retina has a large impact on perceived visual contrast. Much past work suggests that negative feedback from horizontal cells to photoreceptor synaptic terminals is important in generating this lateral inhibition, but the molecular mechanisms mediating this feedback remain unclear. This thesis will survey work focusing on the hypothesis that proton release from horizontal cells is the key molecular player in generating negative feedback from horizontal cells to photoreceptors. According to this hypothesis, protons released from horizontal cells bind to calcium channels on photoreceptor synaptic terminals, leading to a decrease in calcium influx and a decrease in the release of neurotransmitter from photoreceptors. There is much evidence that changes in extracellular acidity significantly affect neuronal signaling in the retina, and this data has been taken as support for the proton hypothesis of lateral inhibition. Recent experiments using optogenetic techniques to measure changes in extracellular acidity during light and chemical stimulation also strongly support the proton hypothesis. However, data measuring proton release from isolated horizontal cells using self-referencing H+-selective electrodes and fluorescent H+ sensors argue strongly against proton release from horizontal cells when stimulated. This thesis will summarize the current status of the proton hypothesis of lateral inhibition and suggest potential alternatives for the functional role that alterations in changes in extracellular acidity may play in retinal function.