University of California, San Francisco
Robert Edwards, Ph.D.
Robert Edwards, M.D.
The Synaptic Basis of Behavior
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, and changes in synaptic function contribute to normal development as well as neural plasticity. Disturbances in synaptic transmission also underlie psychiatric illness and neurological 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 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. Third, recent work from our and other labs has also 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, and characterize the mechanisms responsible.
Fourth, we study the mechanisms responsible for sorting proteins to a secretory pathway capable of regulated release. An RNAi screen in S2 cells has identified a small number of proteins involved in this process, and we are currently pursuing the role of adaptor protein AP-3.
Fifth, 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.
Sixth, how does synaptic function contribute to neural degeneration? In particular, we wish to understand how presynaptic mechanisms influence the pathogenesis of Parkinsonís 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 Parkinsonís disease (PD), and are working now to understand how this and other presynaptic mechanisms influence this form of toxicity. We recently found that ?-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
1) the biophysical properties of synaptic vesicles
2) molecular characterization of vesicular neurotransmitter transporters
3) the physiological role of somatodendritic dopamine release
4) the regulation of neurotransmitter release from dendrites
5) biogenesis of the regulated secretory pathway
6) the role of bulk endocytosis at the nerve terminal
7) the role of glutamate release from neurons that also release another transmitter
8) the function of alpha-synuclein at the nerve terminal and in Parkinson's disease
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., Sirkis, D., Edwards, R.H. 2010. RNAi screen identifies a role for adaptor protein 3 in sorting to the regulated secretory pathway. J. Cell Biol. 191, 1173-1187.
Higley, M.J., Gittis, A.H., Oldenburg, I.A., Balthasar, N., Seal, R.P., Edwards, R.H., Lowell, B.B., Kreitzer, A.C., and Sabatini, B.L. 2011. Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum. PLoS One 6, e19155.
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.
Koch, S.M., Dela Cruz, C.G., Hnasko, T.S., Edwards, R.H., Huberman, A.D., and Ullian, E.M. (2011). Pathway-specific genetic attenuation of glutamate release alters select features of competition-based visual circuit refinement. Neuron 71, 235-242.
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.
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