Robert Edwards, MD

Professor
Department of Neurology and Physiology
+1 415 502-5688
Research Overview: 


The Synaptic Basis of Behavior and Neuropsychiatric Disease

            Synapses endow neural circuits with the capacity to process and store information.  Defects in the molecular components required for synaptic transmission underlie many forms of neuropsychiatric disease, from major mental illness to neural degeneration.  However, the molecular basis for basic features of synaptic transmission remain poorly understood, and in particular those involved in neurotransmitter release.  

            The regulated exocytosis of classical neurotransmitters requires transport into synaptic vesicles, and we identified three families of proteins responsible for this activity.  Vesicular monoamine transport protects against a parkinsonian toxin, implicating this activity in neurodegeneration as well as behavior.  Vesicular glutamate transport determines the quantal response to release of a single synaptic vesicle and exhibits both unusual allosteric regulation by Cl- and H+ and an associated Cl- conductance. We use a combination of biochemical, structural and physiological methods to determine the mechanisms responsible and elucidate their role in neurotransmission. 

            The localization of vesicle transporters also defines the membranes capable of regulated release.  Using them, we found that multiple neuronal populations release two classical neurotransmitters.  Recently, we also found that individual neurons release the two transmitters with different properties, indicating storage in different synaptic vesicles and enabling them to extract different information from neural firing.  The mechanism involves differences in coupling to presynaptic calcium channels.  We also find that the two vesicle populations form through distinct recycling pathways. Thus, the mechanism of endocytosis determines the properties of release.  We now wish to understand how the formation of these vesicles endows them with the properties of release, how the different information extracted from firing rate contributes to behavior and what regulates these mechanisms. 

            In contrast to small synaptic vesicles that release classical neurotransmitters, large dense core vesicles release peptide hormones (such as insulin), neural peptides and some growth factors.  However, the mechanisms that regulate their release and their assembly remain major questions. Using new methods to image the exocytosis of LDCVs at high temporal and spatial resolution, we have identified properties that influence the kinetics of release.  We have also identified machinery involved in the biogenesis of LDCVs. We now wish to determine how the formation of LDCVs endows them with the properties of release and how these mechanisms contribute to normal physiology and disesase,, from diabetes to psychiatric disease. 

            Pursuing the role of neurotransmitter release in Parkinson’s disease (PD), we also study the presynaptic protein alpha-synuclein.  Synuclein has a causative role in PD and seems involved in essentially all forms of the disorder.  Like many other proteins implicated in neural degeneration, however, the function of synuclein remains poorly understood.  Recently, we found that it influences behavior of the fusion pore formed during regulated exocytosis.  We now use a combination of live imaging and molecular biology to explore the mechanisms responsible  and their role in degeneration. 


Lab members:

Postdoctoral Fellows

Jacob Eriksen

Ph.D., University of Copenhagen

 

Ignacio Ibanez

Ph.D., University of Barcelona

 

Shweta Jain

Ph.D., National Centre for Biological Sciences, Bangalore

 

Fei Li

Ph.D., Michigan State University

 

James Maas

M.D., Ph.D., Washington University

 

Gautam Runwal

Ph.D., Cambridge University

 

Katlin Silm

Ph.D., Universite Pierre et Marie Curie, Paris

 

Hongfei Xu

Ph.D., Qingdao University

 

Pengcheng Zhang

Ph.D., UC Berkeley

 

Lab Manager

Samir Batarni

B.S., UC Davis

 

Primary Thematic Area: 
Neurobiology
Secondary Thematic Area: 
None
Research Summary: 
The Molecular Basis of Neurotransmitter Release and Its Role in Synaptic Physiology, Behavior and Disease

Websites

Featured Publications: 

Neural activity controls the synaptic accumulation of alpha-synuclein.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Fortin DL, Nemani VM, Voglmaier SM, Anthony MD, Ryan TA, Edwards RH

Distinct endocytic pathways control the rate and extent of synaptic vesicle protein recycling.

Neuron

Voglmaier SM, Kam K, Yang H, Fortin DL, Hua Z, Nicoll RA, Edwards RH

Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.

Neuron

Seal RP, Akil O, Yi E, Weber CM, Grant L, Yoo J, Clause A, Kandler K, Noebels JL, Glowatzki E, Lustig LR, Edwards RH

Optical reporters for the conformation of alpha-synuclein reveal a specific interaction with mitochondria.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Nakamura K, Nemani VM, Wallender EK, Kaehlcke K, Ott M, Edwards RH

Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors.

Nature

Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH

Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis.

Neuron

Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH

Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo.

Neuron

Hnasko TS, Chuhma N, Zhang H, Goh GY, Sulzer D, Palmiter RD, Rayport S, Edwards RH

Vesicular monoamine and glutamate transporters select distinct synaptic vesicle recycling pathways.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Onoa B, Li H, Gagnon-Bartsch JA, Elias LA, Edwards RH

Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein.

The Journal of biological chemistry

Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K, Munishkina L, Zhang J, Gardner B, Wakabayashi J, Sesaki H, Cheng Y, Finkbeiner S, Nussbaum RL, Masliah E, Edwards RH

v-SNARE composition distinguishes synaptic vesicle pools.

Neuron

Hua Z, Leal-Ortiz S, Foss SM, Waites CL, Garner CC, Voglmaier SM, Edwards RH

Presynaptic regulation of quantal size: K+/H+ exchange stimulates vesicular glutamate transport.

Nature neuroscience

Goh GY, Huang H, Ullman J, Borre L, Hnasko TS, Trussell LO, Edwards RH

Ventral tegmental area glutamate neurons: electrophysiological properties and projections.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Hnasko TS, Hjelmstad GO, Fields HL, Edwards RH

Multiple dileucine-like motifs direct VGLUT1 trafficking.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Foss SM, Li H, Santos MS, Edwards RH, Voglmaier SM

Self-assembly of VPS41 promotes sorting required for biogenesis of the regulated secretory pathway.

Developmental cell

Asensio CS, Sirkis DW, Maas JW, Egami K, To TL, Brodsky FM, Shu X, Cheng Y, Edwards RH

Efficient, complete deletion of synaptic proteins using CRISPR.

Neuron

Incontro S, Asensio CS, Edwards RH, Nicoll RA

Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.

Neuron

Eriksen J, Chang R, McGregor M, Silm K, Suzuki T, Edwards RH

Endogenous Leucine-Rich Repeat Kinase 2 Slows Synaptic Vesicle Recycling in Striatal Neurons.

Frontiers in synaptic neuroscience

Maas JW, Yang J, Edwards RH

a-Synuclein promotes dilation of the exocytotic fusion pore.

Nature neuroscience

Logan T, Bendor J, Toupin C, Thorn K, Edwards RH

A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry.

Nature communications

Ullman JC, Yang J, Sullivan M, Bendor J, Levy J, Pham E, Silm K, Seifikar H, Sohal VS, Nicoll RA, Edwards RH

Synaptic Vesicle Recycling Pathway Determines Neurotransmitter Content and Release Properties.

Neuron

Silm K, Yang J, Marcott PF, Asensio CS, Eriksen J, Guthrie DA, Newman AH, Ford CP, Edwards RH

Structures suggest a mechanism for energy coupling by a family of organic anion transporters.

PLoS biology

Leano JB, Batarni S, Eriksen J, Juge N, Pak JE, Kimura-Someya T, Robles-Colmenares Y, Moriyama Y, Stroud RM, Edwards RH

Ion transport and regulation in a synaptic vesicle glutamate transporter.

Science (New York, N.Y.)

Li F, Eriksen J, Finer-Moore J, Chang R, Nguyen P, Bowen A, Myasnikov A, Yu Z, Bulkley D, Cheng Y, Edwards RH, Stroud RM