Robert Edwards, MD

Professor
Department of Neurology
+1 415 502-5687

The Synaptic Basis of Behavior

        We wish to understand how synapses sculpt the activity of neural circuits.  We have a particular interest in the mechanisms that regulate neurotransmitter release because this process potently controls the flow of information at synapses.  In terms of strategy, we use a combination of molecular biology, biochemistry and biophysics to elucidate physiological mechanism.  

        What determines the amount of transmitter released per synaptic vesicle, or quantal size, 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 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 in biophysical detail. We have also begun to identify mechanisms that regulate transport activity, with important implications for the regulation of synaptic strength. 

        Synaptic vesicles belong to functionally distinct pools, but the molecular basis for these pools remains unknown.  We have begun to identify the molecules that distinguish among vesicle pools, and are now using these differences to understand the function of different pools in synaptic transmission and development.  

        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, physiology and behavior.       

        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.   

        How do proteins sort to a pathway capable of regulated exocytosis?  In contrast to small synaptic vesicles that release classical neurotransmitters, large dense core vesicles release peptide hormones, neural peptides and growth factors.  However, the mechanism by which they form has remained a major question in cell biology.  We have recently identified some of the first components of the cytosolic machinery that produce dense core vesicles, and are now characterizing their activity through a combination of biochemistry and live cell imaging. 

 

 

Lab members:
 
Postdoctoral Fellows
Jacob Bendor
Ph.D, Rockefeller
 
Jacob Eriksen
Ph.D., University of Copenhagen
 
Brad Heller
Ph.D., New York University
 
Shweta Jain
Ph.D., National Centre for Biological Sciences, Bangalore
 
Mikhail Khvotchev
Ph.D., Moscow University
 
James Maas
M.D., Ph.D., Washington University
 
Katlin Silm
Ph.D., Universite Pierre et Marie Curie, Paris
 
Jing Yang
Ph.D., Chinese Academy of Sciences, Shanghai
 
  
Students
Roger Chang
B.S., Washington University
 
Todd Logan
B.S., MIT
 
Julie Ullman
B.S., Cornell
 
 
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: 

Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.

Neuron

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

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

v-SNARE composition distinguishes synaptic vesicle pools.

Neuron

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