Abstract
Purpose: :
Cones and horizontal cells (HCs) have a reciprocal synapse that underlies lateral inhibition and establishes the antagonistic center-surround organization of the visual system. Cones transmit to HCs through an excitatory synapse and HCs feedback to cones through an inhibitory synapse. Here we report that HCs also transmit a positive feedback signal that accelerates neurotransmitter release from cone terminals.
Methods: :
The rate of cone synaptic release was monitored by: 1) Optical imaging the synaptic vesicle dye FM1-43, and 2) Electrophysiological recordings from HCs to measure the frequency of mEPSCs, which reflect photoreceptor release. Changes in Ca2+ were measured with a Ca2+-indicator dye.
Results: :
Opposite to negative feedback predictions, activation of AMPA receptors accelerates cone FM1-43 release in all retinas tested (lizard, salamander, zebrafish, and rabbit). AMPA had no effect on isolated cones, and laser ablation of HCs in retinal slices eliminated the effect, suggesting that HCs are required. The AMPA receptor antagonist DNQX slowed cone release, indicating that ambient glutamate promotes release. Therefore positive feedback is physiologically relevant.Local activation of HC AMPA receptors causes a cell-wide depolarization and a localized rise in Ca2+. Uncaging of Ca2+ within an HC increases mEPCS frequency, whereas depolarizing HCs decreases mEPSC frequency. Hence positive and negative feedback are both initiated by HC AMPA receptors, but different intracellular HC signals mediate each of the two processes. Negative and positive feedback reduce and increase cone terminal Ca2+, respectively. However, modulation of voltage-gated Ca2+ channels mediate negative feedback, whereas activation of a voltage-insensitive channel mediates positive feedback. The nature of this channel and the identity of the HC positive feedback signal remain to be determined.
Conclusions: :
HCs transmit distinct positive and negative feedback signals to cones. Positive feedback is spatially constrained to active HC-cone synapses, whereas negative feedback spreads to affect surrounding cones. By locally offsetting negative feedback, positive feedback may amplify photoreceptor synaptic release without sacrificing HC-mediated contrast enhancement.
Keywords: synapse • retina: distal (photoreceptors, horizontal cells, bipolar cells) • excitatory neurotransmitters