• chelation;
  • glutamate excitotoxicity;
  • ionic zinc;
  • retinal histology;
  • cytoprotection


Thumbnail image of graphical abstract

Our recent studies have shown that endogenous zinc, co-released with glutamate from the synaptic terminals of vertebrate retinal photoreceptors, provides a feedback mechanism that reduces calcium entry and the concomitant vesicular release of glutamate. We hypothesized that zinc feedback may serve to protect the retina from glutamate excitotoxicity, and conducted in vivo experiments on the retina of the skate (Raja erinacea) to determine the effects of removing endogenous zinc by chelation. These studies showed that removal of zinc by injecting the zinc chelator histidine results in inner retinal damage similar to that induced by the glutamate receptor agonist kainic acid. In contrast, when an equimolar quantity of zinc followed the injection of histidine, the retinal cells were unaffected. Our results are a good indication that zinc, co-released with glutamate by photoreceptors, provides an auto-feedback system that plays an important cytoprotective role in the retina.

Recent studies show that endogenous photoreceptor zinc, co-released with glutamate, provides feedback that reduces calcium entry at photoreceptor terminals, thereby regulating vesicular transmitter release. The experiments reported here provide evidence that the in vivo removal of endogenous zinc by chelation results in inner retinal glutamate toxicity. Thus, zinc auto-feedback likely plays a cytoprotective role important to retinal health and disease.