Horizontal Cell Feedback to Cone Photoreceptors in Mammalian Retina: Novel Insights From the GABA-pH Hybrid Model

Abstract

How neurons in the eye feed signals back to photoreceptors to optimize sensitivity to patterns of light appears to be mediated by one or more unconventional mechanisms. Via these mechanisms, horizontal cells control photoreceptor synaptic gain and enhance key aspects of temporal and spatial center-surround receptive field antagonism. After the transduction of light energy into an electrical signal in photoreceptors, the next key task in visual processing is the transmission of an optimized signal to the follower neurons in the retina. For this to happen, the release of the excitatory neurotransmitter glutamate from photoreceptors is carefully regulated via horizontal cell feedback, which acts as a thermostat to keep the synaptic transmission in an optimal range during changes to light patterns and intensities. Novel findings of a recently described model that casts a classical neurotransmitter system together with ion transport mechanisms to adjust the alkaline milieu outside the synapse are reviewed. This novel inter-neuronal messaging system carries feedback signals using two separate, but interwoven regulated systems. The complex interplay between these two signaling modalities, creating synaptic modulation-at-a-distance, has obscured it’s being defined. The foundations of our understanding of the feedback mechanism from horizontal cells to photoreceptors have been long established: Horizontal cells have broad receptive fields, suitable for providing surround inhibition, their membrane potential, a function of stimulus intensity and size, regulates inhibition of photoreceptor voltage-gated Ca 2+ channels, and strong artificial pH buffering eliminates this action. This review compares and contrasts models of how these foundations are linked, focusing on a recent report in mammals that shows tonic horizontal cell release of GABA activating Cl − and HCO 3 − permeable GABA autoreceptors. The membrane potential of horizontal cells provides the driving force for GABAR-mediated HCO 3 − efflux, alkalinizing the cleft when horizontal cells are hyperpolarized by light or adding to their depolarization in darkness and contributing to cleft acidification via NHE-mediated H + efflux. This model challenges interpretations of earlier studies that were considered to rule out a role for GABA in feedback to cones.

Vesicular Release of GABA by Mammalian Horizontal Cells Mediates Inhibitory Output to Photoreceptors

“…Grove et al (2019) extended the findings in Hirano et al (2016a) by showing that GABA release by horizontal cells acts back onto its own GABA receptors, and that the GABA release (and cone Ca channel modulation) is abolished in Cx57-VGAT −/− horizontal cells, concluding that the bicarbonate flux through these tonic GABA receptors regulates the synaptic cleft pH. The full hybrid GABA-pH model is much more detailed (see Figure 8, Grove et al, 2019; Figure 12, Barnes et al, 2020), including roles for sodium-proton exchangers (NHEs), the bicarbonate equilibrium potential and horizontal cell membrane potential excursions induced by GABA and glutamate (Grove et al, 2019;Barnes et al, 2020).…”

“…These include the presence and synthesis of GABA as a neurotransmitter, the essential molecular machinery for vesicular release, the structural basis of vesicular release, namely synaptic vesicles, and the regulated fusion and recycling of synaptic vesicles in mammalian horizontal cells. These findings show that the cellular mechanism underlying feedback inhibition in mammals involves vesicular GABA release by horizontal cells, and this stands to support a new GABA-pH hybrid model wherein autaptic reception of GABA by horizontal cells regulates pH in the synaptic cleft via depolarization and the bicarbonate permeability of the GABA receptors, resulting in the modulation of presynaptic calcium channels in photoreceptors (Grove et al, 2019;Barnes et al, 2020).…”

“…GABA and/or muscimol application activated ionotropic GABA A receptors and elicited chloride currents, blocked by bicuculline and picrotoxin, in whole-cell recordings of isolated rabbit, mouse, and rat horizontal cells (Blanco and de la Villa, 1999;Feigenspan and Weiler, 2004;Liu et al, 2013). In mouse horizontal cells, we showed distinct immunolabeling for GABA A ρ ρ2 subunit localized predominantly to their endings at its axon terminals within rod spherules and at its dendrites at cone pedicles (Grove et al, 2019;Barnes et al, 2020), indicating the presence of GABA A ρ receptors. Notable characteristics of GABA A ρ receptors include high affinity for GABA and nondesensitizing currents, capable of producing tonic currents at ambient levels of interstitial GABA, similar to extrasynaptic GABA receptors in other areas of the CNS (Bormann and Feigenspan, 1995;Bormann, 2000;Farrant and Nusser, 2005).…”

“…Transmitter release by a regulated vesicular mechanism would be highly advantageous for fine control of feedback and feedforward action in the outer retina, as there are multiple molecular control points to modulate secretion from horizontal cells that utilizes the bicarbonate permeability of GABA A receptors to regulate cleft pH (Grove et al, 2019;Barnes et al, 2020). For instance, VGAT's dependence on a proton gradient for GABA uptake would influence vesicular GABA concentrations (Reimer et al, 1998) and, by extension, postsynaptic responses.…”

“…The presence of VGAT in horizontal cell synaptic endings suggested that these unconventional neurons may release the neurotransmitter GABA via vesicular release. When VGAT was deleted from horizontal cells, these cells failed to feedback to photoreceptors (Hirano et al, 2016a) and the same mouse line revealed a lack of autaptic GABA reception by horizontal cells and no influence on cone calcium channels (Grove et al, 2019;Barnes et al, 2020), ending debate, at least in mammalian retinas, about whether horizontal cells utilize vesicular GABA release to send feedback to photoreceptors. Here we marshal evidence for the hypothesis that mammalian horizontal cells possess the cellular structures and proteins that mediate vesicular transmitter release.…”