Robert Edwards, MD


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.  The amount of neurotransmitter stored per synaptic vesicle determines both the extent and location of receptors activated by release but remains poorly understood.  What controls the tonic release of neurotransmitter, either by spontaneous vesicle fusion or by non-vesicular efflux across the plasma membrane?  What is the molecular basis for the corelease of two classical transmitters by one neuron, and for synaptic vesicle pools?  How does the presynaptic protein a-synuclein cause Parkinson’s disease? 

            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 over-expression of synuclein inhibits regulated exocytosis, but the endogenous protein normally functions to promote dilation of the exocytotic fusion pore.  Surprisingly, the mutations that cause Parkinson’s disease appear to affect the normal function of this protein. 

            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. 


Lab Members

Postdoctoral Fellows
Jacob Bendor
Ph.D., Rockefeller

Jacob Eriksen
Ph.D., University of Copenhagen

Shweta Jain
Ph.D., National Centre for Biological Sciences, Bangalore, India

Mikhail Khvotchev
Ph.D., Moscow University

Fei Li
Ph.D., Michigan State University

James Maas
M.D., Ph.D., Washington University

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

Pengcheng Zhang
Ph.D.. UC Berkeley

Roger Chang
B.S., Washington University

Lab Manager
Samir Batarni
B.S., UC Davis


Lab Website