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Neuroscience Graduate Program at UCSF

Faculty - Robert Edwards, M.D.

The Synaptic Basis of Behavior


Research Description

We wish to understand the cellular and molecular mechanisms involved in neurotransmitter release and how they contribute to physiology, behavior and disease.  Different synapses process information in distinct ways, but we do not understand the basis for these differences or their role in physiology and behavior.  Changes in synaptic function also contribute to normal development as well as neural plasticity, and underlie both psychiatric illness and neurodegenerative disease.  To elucidate the molecular basis for transmitter release, and to understand how the properties of release contribute to normal behavior and disease, we use a combination of biochemistry in vitro, optical imaging in primary neuronal culture and genetic manipulation in vivo.  The lab focuses on several fundamental questions. 

First, what regulates the amount of transmitter per vesicle (or quantal size), the elementary unit in synaptic transmission?  We have previously identified three distinct protein families that transport neurotransmitters into secretory vesicles.  Using a variety of biochemical and biophysical methods including fluorescence measurements and electrophysiology, we are characterizing the properties of these proteins, and exploring the role of other synaptic vesicle components in vesicle filling and other aspects of the synaptic vesicle cycle. 

Second, we wish to understand the mechanism and role of transmitter release from dendrites.  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.  Through a combination of optical imaging in vitro and genetic manipulation in vivo, we hope to elucidate the physiological role of dendritic dopamine release in synaptic plasticity and determine its behavioral role in the reward pathway subverted by drug abuse. 

Third, we are studying the molecular basis for synaptic vesicle pools.  It is well known that synaptic vesicles belong to functionally distinct pools, but the basis for these differences and the role of these pools in synaptic physiology and development remains unclear.  We are testing the possibility that different recycling pathways produce biochemically distinct synaptic vesicles. 

Fourth, recent work from our and other labs has shown that many neurons associated with the release of a different classical transmitter (such as dopamine, serotonin, acetylcholine and GABA) also release glutamate.  We now wish to understand the role of glutamate corelease in physiology and behavior.  

Fifth, how does synaptic function contribute to neural degeneration?  In particular, we wish to understand how presynaptic mechanisms influence 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 (PD), and are working now to understand how this and other presynaptic mechanisms influence this form of toxicity.   We recently found that a-synuclein, a protein implicated in PD, inhibits transmitter release, and now wish to understand the mechanism as well as explore the relationship to neural degeneration.     

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Current Projects

See research description

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Lab Members

Postdoctoral Fellows
Cedric Asensio
Ph.D., University of Geneva

Jacob Bendor
Ph.D., Rockefeller

Jacob Eriksen
Ph.D., University of Copenhagen

Narinobu Juge
Ph.D., Okayama University

Mikhail Khvotchev
Ph.D., Russian Academy of Sciences, Moscow

James Maas
M.D., Ph.D., Washington University

Wei Zou
Ph.D., National Institute of Biological Sciences, Beijing

Students
Sarah Foss
B.S., University of Chicago

Todd Logan
B.S., MIT

Daniel Sirkis
B.S., University of Wisconsin

Julie Ullman
B.S., Cornell

Lab Manager
Daniel Johengen
B.S., UC Santa Cruz

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Selected Publications

Fortin, D.L., Nemani, V.M., Voglmaier, S.M., Anthony, M.D., Ryan, T.A., Edwards, R.H.  2005.  Neural activity controls the synaptic accumulation of a-synuclein.  J. Neurosci. 25, 10913-10921.

Li, H., Waites, C.L., Staal, R.G., Dobryy, Y., Park, J., Sulzer, D.L. Edwards, R.H.  2005.  Sorting of vesicular monoamine transporter 2 to the regulated secretory pathway confers the somatodendritic exocytosis of monoamines.  Neuron 48, 619-633.

Voglmaier, S.M., Kam, K., Yang, H., Fortin, D.L., Hua, Z., Nicoll, R.A., Edwards, R.H.  2006.  Distinct endocytic pathways control the rate and extent of synaptic vesicle recycling.  Neuron 51, 71-84.   

Edwards, R.H.  2007.  The neurotransmitter cycle and quantal size.   Neuron 55, 835-858.

Seal, R.P., Akil, O., Yi, E., Weber, C.M., Grant, L., Yoo, J., Clause, A., Kandler, K., Noebels, J.L., Glowatzki, E., Lustig, L.R., Edwards, R.H.  2008.  Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.  Neuron 57, 263-275. 

Nakamura, K., Nemani, V.M., Kaehlcke, K., Ott, M. and Edwards, R.H. 2008. Optical reporters for the conformation of a-synuclein reveal a specific interaction with mitochondria.  J. Neurosci.28, 12305-12317. 

Mosharov EV, Larsen KE, Phillips KA, Wilson K, Kanter E., Schmitz Y., Krantz D.E., Edwards R.H., Sulzer D. 2009. Interplay between cytosolic dopamine, calcium and lpha-synuclein causes selective death of substantia nigra neurons. Neuron 62,  218-229. 

Gubernator, N.G., Zhang, H., Staal, R.G.W., Mosharov, E.V., Pereira, D., Yue, M., Balsanek, V., Vadola, P.A., Mukherjee, B., Edwards, R.H., Sulzer, D., Sames, D.  2009. Activity-dependent heterogeneity of dopamine release at individual presynaptic terminals visualized with fluorescent false neurotransmitters. Science 324, 1441-4. 

Seal, R.P., Wang, X.,  Guan, Y., Raja, S.N., Woodbury, C.J., Basbaum, A.I. and Edwards, R.H.  2009. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors.  Nature 462, 651-655. 

Nemani, V.M., Lu, W., Berge, V., Nakamura, K., Onoa, B., Lee, M.K., Chaudhry, F.A., Nicoll, R.A. and Edwards, R.H.  2010.  Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis.  Neuron 65, 66-79.

Noh, J., Seal, R.P., Garver, J.A., Edwards, R.H., Kandler, K.  2010. Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map. Nat. Neurosci. 13, 232-8.

Hnasko, T.S., Chuhma, N., Zhang, H., Goh, G.A., Sulzer, D., Palmiter, R.D., Rayport, S. and Edwards, R.H.  2010.  Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo.  Neuron 65, 643-656.

Onoa, B.,  Li, H., Gagnon-Bartsch, J.A., Laura A.B. Elias and Edwards, R.H.  2010.  Vesicular monoamine and glutamate transporters select distinct synaptic vesicle recycling pathways.  J. Neurosci. 30, 7917-7927. 

Stuber, G.D., Hnasko, T., Britt, J.P., Edwards, R.H. and Bonci, A.  2010.  Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum co-release glutamate.  J. Neurosci. 30, 8229-8233. 

Asensio, C.A., Sirkis, D.W., Edwards, R.H.  RNAi screen identifies a role for adaptor protein AP-3 in sorting to the regulated secretory pathway.  J. Cell Biol. 191, 1173-1187.

Nakamura, K., Nemani, V.M., Azarbal, F., Skibinski, G., Levy, J.M., Egami, K., Munishkina, L., Zhang, J., Gardner, B., Wakabayashi, J. et al.  2011. Direct membrane association drives mitochondrial fission by the Parkinson Disease-associated protein alpha-synuclein. J. Biol. Chem. (paper of the week), 286, 20710-20726.

Hua, Z., Leal-Ortiz, S., Foss, S.M., Waites, C.L., Garner, C.C.,  Voglmaier, S.,M.,  Edwards, R.H.  2011.    v-SNARE composition distinguishes synaptic vesicle pools.  Neuron 71, 474-487.

Goh, G.,Y. Huang, H., Ullman, J., Borre, L., Hnasko, T.S., Trussell, L.O. and Edwards, R.H.  2011.  Presynaptic regulation of quantal size:  K+/H+ exchange stimulates glutamate storage by increasing membrane potential.  Nat. Neurosci. 14, 1285-1292.

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Robert Edwards, M.D.



Email

robert.edwards@ucsf.edu

Phone

415-502-5687

Fax: 415-502-8644

Office Address

UCSF Box 2140
Genentech Hall
600 16th Street, GH-N272B
San Francisco, CA 94158

Other Websites

Biomedical Sciences Graduate Program

Institute for Neurodegenerative Diseases

PIBS Website

TETRAD

The Wheeler Center for the Neurobiology of Addiction