Vision Research Laboratory of Richard Chappell
|Address||MBL, 7 MBL Street, Woods Hole, MA 02543|
Research goals are directed toward understanding the roles of zinc in vision and disease. Over the past decade, our investigations have established a role for reactive zinc (Zn2+) as a neuromodulator at the level of the outer plexiform layer of the vertebrate retina. Upon discovering a biphasic change in the sensitivity of the GABA response of isolated skate bipolar cells in the presence of increasing concentrations of zinc (enhanced by low concentrations but reduced by higher concentrations), we found histological evidence for the presence of Zn2+ in the region of the skate photoreceptor terminals where its release could be playing a physiological role. Significant evidence for such a role was established when we found that reducing the concentration of endogenous zinc in the skate retina by application of the zinc chelator histidine resulted in a near doubling of the b-wave, the prominent “ON” component of clinically important electroretinogram (ERG). In subsequent studies, we established the presence of the zinc transporter-3 (ZnT3), which is associated with transport of zinc into synaptic vesicles, in that region of the retina. Using zinc-sensitive dyes, we then monitored zinc release from isolated photoreceptor terminals showing that it was induced by depolarization and modulated by light.
We are now embarked on studies to determine mechanisms by which this zinc release is acting to modulate transmission at this first stage in the processing of visual information in the retina. The hypothesis that zinc released provides feedback at the photoreceptor terminals by modulation of the calcium entry involved in its vesicular release along with glutamate is of particular interest. Such feedback may provide a way to reset the gain of the photoreceptor synapse as the mean level of light intensity increases over several log units. This zinc feedback may also serve to reduce the amount of glutamate released in the dark when photoreceptors are maximally depolarized and the release of the potentially excitotoxic photoreceptor neurotransmitter glutamate is not needed for vision. Our preliminary studies using intraocular injection of a zinc chelator (TPEN) to remove endogenous free zinc have provided histological evidence typical of glutamate excitotoxicity in retinal neurons. This finding suggests that zinc can indeed play a cytoprotective role in the retina. If so, zinc may well be a factor in some forms of retinal disease, and it is worth noting that zinc is already being prescribed clinically in one form of age-related macular degeneration of the retina.
Zinc appears to be an important factor throughout the nervous system. Zinc deficiency is associated with one form of night blindness. It is known to play a role in the hippocampus, an important site of learning and memory. There is evidence that it may be a factor in certain forms of dementia and diseases of aging, including Alzheimer’s disease. The retina provides a well-defined, suitably isolated region of neuronal material in which mechanisms of zinc, as a neuromodulator, can be investigated. Findings will provide not only a better understanding of visual information processing, but also new insight into the role it plays elsewhere in the nervous system.