David R. Copenhagen

Research Interests

Synaptic Transmission and Communication in Retina: Pathways, Processing, Cellular Mechanisms and Development

Research Summary

Synaptic Transmission and Communication in Retina: Pathways, Processing, Cellular Mechanisms and Development

The retina serves to detect and preprocess visual images. Detection is mediated by rods and cones which not only exhibit an exquisite sensitivity to dim light but also "adapt" their operating range to cover changes in ambient light intensities that extend over more than 10 log units. The limitations in information transfer from the eye to the brain via the optic nerve (approx. 1 million fibers with a transfer rate of around 100 bits/sec per fiber) forces the retinal circuitry to heavily process the visual image by extracting only the most salient features of the visual scene. Our laboratory is interested in the synaptic and cellular machinery that enables the retina to perform its signal processing. One major effort in our lab studies how calcium is regulated in the retinal neurons. The release of neurotransmitters requires a localized rise and fall of calcium in synaptic terminals. We are presently focussing on how calcium is buffered in and extruded from the retinal cells. We use both optical imaging and electrophysiology to examine calcium diffusion and control in single cells. A second major effort in the lab centers on how glutamate, the principal excitatory neurotransmitter of the retina, and the brain, is regulated. Glutamate is pumped into small (~ 50 nm) vesicles in synaptic terminals. When the glutamate is released via calcium-dependent exocytosis, it must be cleared from the synaptic cleft very rapidly in order to maintain the frequency response of the synapses. This clearance is accomplished by transporters which pump glutamate into glial cells. In these non-neuronal cells, glutamate is converted enzymatically to glutamine which is then transported back to the neurons for re-use. We are focussing on identification and characterization of two principal transporters in this glutamate/glutamine pathway: The glutamine transporters that pump glutamine out of the glial cells and into the neurons and the vesicular glutamate transporters that concentrate glutamate molecules into the synaptic vesicles. To characterize these pathways, we are employing techniques ranging from electroretinographic recordings light-evoked field potentials to single cell optical and electrophysiological recordings to immunolocalization with specific antibodies to molecular biology. A third ongoing interest of our lab centers on how the synaptic pathways develop at times well after birth. We find that that there are extensive changes in the synaptic pathways of the inner retina after eye opening in rats and mice. Most interesting is that this development requires normal vision. If animals are raised in darkness, synaptic development is impeded. We are seeking to discover what part of the synaptic circuit requires light-evoked activity and what cellular components of the synaptic machinery are affected. For this purpose we are utilizing multi-electrode arrays to simultaneously record from up to 60 or 70 ganglion cells, the output neurons of the retina. In addition we are using immunolocalization and patch clamp electrophysiology to examine how cellular function is affected.

Selected Publications

Krizaj D, Copenhagen DR. Compartmentalization of calcium extrusion mechanisms in the outer and inner segments of photoreceptors. Neuron 1998 21:249-56.

Tain N, Copenhagen, DR. Visual deprivation alters development of synaptic function in inner retina after eye opening. Neuron (in press, Nov. 8, 2001 publication date)

Chaudhry FA, Reimer RJ, Krizaj D, Barber D, Copenhagen DR and Edwards RH. Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission. Cell 1999 99:769-80.