Abstract
The stream of visual information sent from photoreceptors to second-order bipolar cells is intercepted by laterally interacting horizontal cells that generate feedback to optimize and improve the efficiency of signal transmission. The mechanisms underlying the regulation of graded photoreceptor synaptic output in this nonspiking network have remained elusive. Here, we analyze with patch clamp recording the novel mechanisms by which horizontal cells control pH in the synaptic cleft to modulate photoreceptor neurotransmitter release. First, we show that mammalian horizontal cells respond to their own GABA release and that the results of this autaptic action affect cone voltage-gated Ca2+ channel (CaV channel) gating through changes in pH. As a proof-of-principle, we demonstrate that chemogenetic manipulation of horizontal cells with exogenous anion channel expression mimics GABA-mediated cone CaV channel inhibition. Activation of these GABA receptor anion channels can depolarize horizontal cells and increase cleft acidity via Na+/H+ exchanger (NHE) proton extrusion, which results in inhibition of cone CaV channels. This action is effectively counteracted when horizontal cells are sufficiently hyperpolarized by increased GABA receptor (GABAR)-mediated HCO3− efflux, alkalinizing the cleft and disinhibiting cone CaV channels. This demonstrates how hybrid actions of GABA operate in parallel to effect voltage-dependent pH changes, a novel mechanism for regulating synaptic output.
Highlights
Vision relies on reliable information transfer from photoreceptors to horizontal and bipolar cells at the first synapse in the visual system [1]
Differences in GABA synthesis between these species are considered to be a result of varying levels of glutamic acid decarboxylase (GAD) [35,48]
When we recorded from horizontal cells lacking vesicular GABA transporter (VGAT) (Cx57-VGAT-KO; Fig 3D), we found TPMPA no longer caused any change in current (Fig 3E and 3F; P = 0.8, n = 5), differing significantly from wild-type (WT) mice (P < 0.001), despite the normal expression of ρ-subunit–containing GABA receptor (GABAR) in horizontal cells of Cx57-VGAT-KO animals (S1 Fig)
Summary
Vision relies on reliable information transfer from photoreceptors to horizontal and bipolar cells at the first synapse in the visual system [1]. Feedback inhibition to cones in fish [15] and macaque [14] is accompanied by a decrease in Ca2+ and Ca2+-activated Cl− conductances, which is inconsistent with a direct ionotropic action on cones of GABA. Rather, these conductance changes are explained by decreased activation of cone CaV channels and their closely linked Ca2+-activated Cl− channels [22,23], which are shown in this report to be indirectly modulated by GABA agonists and antagonists in a novel manner
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