Kinetics of Inhibitory Feedback from Horizontal Cells to Photoreceptors: Implications for an Ephaptic Mechanism

Abstract

Inhibitory feedback from horizontal cells (HCs) to cones generates center-surround receptive fields and color opponency in the retina. Mechanisms of HC feedback remain unsettled, but one hypothesis proposes that an ephaptic mechanism may alter the extracellular electrical field surrounding photoreceptor synaptic terminals, thereby altering Ca 2ϩ channel activity and photoreceptor output. An ephaptic voltage change produced by current flowing through open channels in the HC membrane should occur with no delay. To test for this mechanism, we measured kinetics of inhibitory feedback currents in Ambystoma tigrinum cones and rods evoked by hyperpolarizing steps applied to synaptically coupled HCs. Hyperpolarizing HCs stimulated inward feedback currents in cones that averaged 8 -9 pA and exhibited a biexponential time course with time constants averaging 14 -17 ms and 120 -220 ms. Measurement of feedback-current kinetics was limited by three factors: (1) HC voltage-clamp speed, (2) cone voltage-clamp speed, and (3) kinetics of Ca 2ϩ channel activation or deactivation in the photoreceptor terminal. These factors totaled ϳ4 -5 ms in cones meaning that the true fast time constants for HC-to-cone feedback currents were 9 -13 ms, slower than expected for ephaptic voltage changes. We also compared speed of feedback to feedforward glutamate release measured at the same cone/HC synapses and found a latency for feedback of 11-14 ms. Inhibitory feedback from HCs to rods was also significantly slower than either measurement kinetics or feedforward release. The finding that inhibitory feedback from HCs to photoreceptors involves a significant delay indicates that it is not due to previously proposed ephaptic mechanisms.

How do horizontal cells ‘talk’ to cone photoreceptors? Different levels of complexity at the cone–horizontal cell synapse

“…Warren et al . () also recorded individual cones, but in contrast to Vroman et al . (), they manipulated the membrane potential of the presynaptic HC directly.…”

“…This, however, is in contrast to a study in which feedback signals in cones displayed a latency of ∼10 ms (Warren et al . ). This discrepancy may have resulted from the different ways HC feedback was evoked in the two studies: Vroman et al .…”

“…; Warren et al . ), which argues against an involvement in light adaptation, a function that is often ascribed to HCs. Adaptation to the ambient light level mostly happens as a modulation of the phototransduction cascade (reviewed by Pugh et al .…”

Sensory Consciousness is Experienced through Amplification of Sensory Stimuli via Lateral Inhibition

“…When the initial image falls on the retina, it undergoes amplification 100,000 times through chemical and electrical transduction during lateral inhibition [33]. Direct electric conduction from one neuron to another (especially those connected laterally) begins at photoreceptor synapses without the need for a neurotransmitter [37]. It has also been suggested that proton concentration carries feedback signal to cones, and is regulated by horizontal cells [38].…”

Quantifying the effect of light activated outer and inner retinal inhibitory pathways on glutamate release from mixed bipolar cells.

“…Inhibitory signals in the OPL and IPL are essential in mediating computational elements of retinal functions, such as forming the classical antagonistic center and surround regions of the receptive fields of GCs (Cook & McReynolds, ; Flores‐Herr, Protti, & Wassle ; Vigh & Witkovsky, ; Werblin, ) or coding for the direction of visual stimulus movement (Caldwell Caldwell, Daw, & Wyatt ). Whereas in the OPL feedback inhibition from HCs to rod (Babai & Thoreson, ) and cone photoreceptors (Hirasawa & Kaneko, ; Verweij, Kamermans, & Spekreijse, ; Warren, Van Hook, Tranchina, & Thoreson, ) might influence BC signaling indirectly, direct GABAergic feed forward HC inputs to mammalian ON BCs (Duebel et al, ) were also documented. The axon terminals of BCs in the IPL receive extensive GABAergic and/or glycinergic feedback inhibition from ACs (Eggers & Lukasiewicz, ; Grimes, ).…”