Robert
Edwards, M.D.
Professor of Neurology
and Physiology



Contact Information:
robert.edwards@ucsf.edu
Tel: (415) 502-5687
Fax: (415) 502-8644
Box 2140, S-268
Genentech Hall
Room N-272B

Links:
Lab website
Neuroscience
Biomedical Sciences
PIBS
Wheeler Center for the Neurobiology of Addiction

Publications:
Selected

The Synaptic Basis of Behavior

The processing of information by the brain occurs at synapses, sites specialized for fast chemical signaling between cells. At the synapse, neurotransmitter released by exocytosis activates postsynaptic receptors, conferring speed of response and the potential for regulation. However, the small number of vesicles available for release at many synapses imposes constraints on synaptic transmission, and requires local recycling of membrane and transmitter to sustain release. In particular, the synapse must balance the magnitude of acute release against the stores available for future release. To understand how the synapse controls these and other properties, we use a combination of biochemistry and optical imaging in primary neuronal culture to elucidate the molecular mechanism, as well as genetic manipulation in vivo to assess the consequences for neural circuits and behavior.

We are studying several basic features of synaptic transmission. First, we wish to understand what regulates the amount of transmitter per vesicle, or quantal size, the elementary unit in synaptic transmission. Using a variety of biochemical and biophysical methods including fluorescence measurements and electrophysiology, we are characterizing the carriers present on synaptic vesicles, identifying the proteins responsible, and testing their physiological significance for synaptic transmission and behavior. Second, we wish to understand the molecular mechanisms involved in regulated dendritic release. In contrast to most classical transmitters, dopamine and neural peptides undergo regulated release from dendrites as well as the axon terminal, and the dendritic release of neurotrophins has been proposed to serve as a retrograde synaptic signal in development and plasticity. Using an optical reporter in dissociated neuronal culture, we are now characterizing the physiological regulation of dendritic release. By manipulating expression in vivo, we hope to elucidate the physiological role of dendritic release in synaptic plasticity and to determine its behavioral role in the reward pathway subverted by drug abuse. In addition, we are have recently found that synaptic vesicles recycle through two distinct pathways, and are now testing the hypothesis that these pathways generate distinct vesicle pools with different properties, including different responses to stimulation. We are also using the genetic manipulation of vesicular glutamate transporters in mice to explore the role of specific neural circuits in behavior. For example, the novel isoform VGLUT3 is expressed by neurons usually associated with a transmitter other than glutamate, and the knock-out exhibits a series of novel phenotypes. We also wish to understand how neurotransmitter release influences the pathogenesis of Parkinson’s disease. We originally identified the vesicular monoamine transporter by virtue of its ability to protect against a neurotoxin that reproduces the selective dopamine loss of Parkinson’s disease, and we are working now to understand how this and other presynaptic mechanisms influence this form of toxicity. In addition, we wish to understand how the presynaptic protein α-synuclein contributes to Parkinson’s disease.

Selected Publications:

Chaudhry, F.A., Reimer, R.J., Krizaj, D., Barber, D., Storm-Mathisen, J., Copenhagen, D.R., Edwards, R.H. 1999. Analysis of an orphan neurotransmitter transporter identifies novel physiological roles for classical amino acid transport System N in nitrogen metabolism and synaptic transmission. Cell 99, 769-780.

Krantz, D.E., Waites, C., Oorschot, V., Liu, Y., Wilson, R.I., Tan, P.K., Klumperman, J., Edwards, R.H. 2000. A phosphorylation site in the vesicular acetylcholine transporter regulates sorting to secretory vesicles. J. Cell Biol. 149, 379-395.

Bellocchio, E. E., Reimer, R. J., Fremeau, R. T. J., and Edwards, R. H. 2000. Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science 289, 957-960.

Waites, C.L., Mehta, A., Tan, P.K., Friesen, E., Thomas, G., Edwards, R.H., Krantz, D.E. 2001. An acidic motif retains vesicular monoamine transporter 2 on large dense core vesicles. J. Cell Biol. 152, 1159-1168.

Fremeau, R.T. Jr., Troyer, M.D., Pahner, I., Nygaard, G.O., Tran, C.H., Reimer, R.J., Bellocchio, E.E., Fortin, D., Storm-Mathisen, J., Edwards, R.H. 2001. The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron 31, 247-260.

Chaudhry, F.A., Krizaj., D., Larsson, P., Reimer, R.J., Wreden, C., Storm-Mathisen, J., Copenhagen, D., Kavanaugh, M., Edwards, R.H. 2001. Coupled and uncoupled proton movement by amino acid transport system N. EMBO J. 20, 7041-7051.