Neuroscience Graduate Program at UCSF
The Synaptic Basis of Behavior
Synapses perform the information processing required for essentially all brain function. To understand how they do this, we study the cellular and molecular mechanisms involved in neurotransmitter release. In general terms, we wish to understand the basic principles that underlie synapse function, anticipating that they will also shed light on development, plasticity and the problems that occur in disease. We are particularly interested in several fundamental questions that remain unanswered.
What determines the amount of transmitter per vesicle, the elementary unit in synaptic transmission? We previously identified three distinct protein families that transport neurotransmitters into secretory vesicles, but their intracellular location has made them very difficult to study. We have now developed a variety of biochemical and biophysical methods including fluorescence measurements and electrophysiology that enable us to characterize their function in considerable detail. We have also begun to identify the mechanisms that regulate their activity.
Synaptic vesicles reside in functionally distinct pools, but the molecular basis for these pools remains unknown. We have begun to identify the molecules that distinguish between the pools, and expect that these will provide the insight needed to understand their function.
Why do many neurons release two classical transmitters, one a neuromodulator such as dopamine and the other either GABA or glutamate? To understand the role of dual release in signalling, we use genetic manipulation in mice together with biochemistry and physiology.
How does synaptic transmission contribute to neural degeneration? The presynaptic protein alpha-synuclein has a causative role in Parkinson’s disease and seems involved in essentially all forms of the disorder. However, the function of synuclein at the nerve terminal remains uncertain. We have found that it inhibits neurotransmitter release, and are now exploring the mechanism.
We are also very interested in exploring the implications of these mechanisms for behavior and disease. To test their role, we use genetic manipulation in mice combined with physiological and behavioral analysis.
See research description
Ph.D., University of Geneva
Ph.D., University of Copenhagen
Ph.D., New York University
Ph.D., Okayama University
M.D., Ph.D., Washington Universit
Ph.D., Universite Pierre et Marie Curie, Paris
Ph.D., Chinese Academy of Sciences, Shanghai
B.S., Washington University
B.S., University of Wisconsin
B.A., UC Berkeley
Hnasko, T.S., Hjelmsted, G.O., Fields, H.L., Edwards, R.H. 2012. Ventral tegmental area glutamate neurons: electrophysiological properties and projections. J. Neurosci. 32, 15076-85.
Sirkis, D.W., Edwards, R.H., Asensio, C.S. 2013. Widespread dysregulation of peptide hormone release in mice lacking adaptor protein AP-3. PloS Genetics 9, e1003812.
Foss, S.M., Li, H., Santos, M.S., Edwards, R.H., and Voglmaier, S.M. (2013). Multiple dileucine-like motifs direct vglut1 trafficking. J. Neurosci. 33, 10647-10660.
Li, H., Fertuzinhos, S., Mohns, E., Hnasko, T.S., Verhage, M., Edwards, R., Sestan, N., and Crair, M.C. (2013). Laminar and columnar development of barrel cortex relies on thalamocortical neurotransmission. Neuron 79, 970-986.
Asensio, C.S., Sirkis, D.W., Maas, J., Egami, K., To, T.-L., Brodsky, F.M., Shu, X., Cheng, Y., Edwards, R.H. (2013) Self-assembly of VPS41 promotes sorting required for biogenesis of the regulated secretory pathway. Dev. Cell. 27, 425-437.
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.
Robert Edwards, M.D.
UCSF Box 2140
600 16th Street, GH-N272B
San Francisco, CA 94158