Differential regulation of cone calcium signals by different horizontal cell feedback mechanisms in the mouse retina

Controlling neurotransmitter release by modulating the presynaptic calcium level is a key mechanism to ensure reliable signal transmission from one neuron to the next. In this study, we investigated how the glutamatergic output of cone photoreceptors (cones) in the mouse retina is shaped by different feedback mechanisms from postsynaptic GABAergic horizontal cells (HCs) using a combination of two-photon calcium imaging and pharmacology at the level of individual cone axon terminals. We provide evidence that hemichannel-mediated (putative ephaptic) feedback sets the cone output gain by defining the basal calcium level, a mechanism that may be crucial for adapting cones to the ambient light level. In contrast, pH-mediated feedback did not modulate the cone basal calcium level but affected the size and shape of light-evoked cone calcium signals in a contrast-dependent way: low-contrast light responses were amplified, whereas high-contrast light responses were reduced. Finally, we provide functional evidence that GABA shapes light-evoked calcium signals in cones. Because we could not localize ionotropic GABA receptors on cone axon terminals using electron microscopy, we suggest that GABA may act through GABA autoreceptors on HCs, thereby possibly modulating hemichannel- and/or pH-mediated feedback. Together, our results suggest that at the cone synapse, hemichannel-mediated (ephaptic) and pH-mediated feedback fulfill distinct functions to adjust the output of cones to changing ambient light levels and stimulus contrasts and that the efficacy of these feedback mechanisms is likely modulated by GABA release in the outer retina.