Neuroscience Graduate Program at UCSF
The Synaptic Basis of Behavior
The quantal release of neurotransmitter underlies information processing by the brain, but the basic mechanisms responsible for this mode of signaling remain poorly understood. What controls the tonic release of neurotransmitter, either by spontaneous vesicle fusion or by non-vesicular efflux across the plasma membrane? What determines the amount of neurotransmitter stored per synaptic vesicle, a poorly understood determinant of quantal size? What is the molecular basis for the corelease of two classical transmitters by one neuron, and for synaptic vesicle pools?
We previously identified three distinct protein families that transport classical 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, live cell imaging and electrophysiology that enable us to characterize their function. We have also begun to identify mechanisms that control transport activity, with important implications for the non-vesicular release of transmitter as well as the regulation of synaptic strength.
Synaptic vesicles reside in functionally distinct pools, and we have begun to identify the molecules that distinguish between vesicle pools. We are now using these differences to understand their physiological role in synaptic transmission and development. To understand why many neurons release two classical transmitters, we use genetic manipulation in mice together with biochemistry and physiology.
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 unknown. We have found that it inhibits neurotransmitter release, and are now elucidating the mechanism responsible.
In addition to classical neurotransmitters, peptide hormones and neural peptides sort to a pathway capable of regulated exocytosis but the mechanism by which they form has remained a major question in eukaryotic cell biology. We have recently identified some of the first components of the cytosolic machinery that produce dense core vesicles, and are now exploring their function using a combination of biochemistry and live cell imaging.
For all of these studies, we are developing systems to explore their role in synaptic transmission using electrophysiology and in behavior using genetic manipulation in mice.
See research description
Ph.D., University of Geneva
Ph.D., University of Copenhagen
Ph.D., New York University
Ph.D., National Centre for Biological Sciences, Bangalore, India
Ph.D., Moscow University
M.D., Ph.D., Washington University
Ph.D., Universite Pierre et Marie Curie, Paris
Ph.D., Chinese Academy of Sciences, Shanghai
B.S., Washington University
B.S., UC Davis
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.
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.
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. 2010. 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.
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.
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.
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.
Incontro, S., Asensio, C.S., Edwards, R.H., and Nicoll, R.A. (2014). Efficient, complete deletion of synaptic proteins using crispr. Neuron 83, 1051-1057.
Herring, B.E., Silm, K., Edwards, R.H., Nicoll, R.A. (2015). Is aspartate an excitatory neurotransmitter? J. Neurosci. 35, 10168-10171.Pathak, D,. Shields, L., Mendelsohn, B.A., Haddad, D., Lin, W., Gerencser, A.A., Kim, H., Brand, M.D., Edwards, R.H., Nakamura, K. (2015). The role of mitochondrially derived ATP in synaptic vesicle recycling. J. Biol. Chem. (paper of the week), epub ahead of print.
Robert Edwards, M.D.
UCSF Box 2140
600 16th Street, GH-N272B
San Francisco, CA 94158