Robert Edwards, MD

Professor
Neurology
415-502-5687

The Synaptic Basis of Behavior

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

            The release of a single synaptic vesicle triggers a postsynaptic response (quantum) that is considered the elementary unit of synaptic transmission, but we know little about what determines the amount of neurotransmitter per vesicle.  The intracellular location of vesicular neurotransmitter transporters has complicated their analysis.  We have developed a variety of biochemical and biophysical methods including whole endosome recording that enable us to characterize their properties and elucidate the mechanisms of regulation. We are also using this information to understand how vesicle filling contributes to synaptic transmission.

            The localization of vesicular neurotransmitter transporters also defines the membranes capable of regulated release.  Using them, we and others have found that many neuronal populations release two classical transmitters.  The function of corelease remains unclear, but we have found that one transmitter can influence the packaging of the other.  In addition, the two transmitters can act as independent signals, raising the possibility of release from different vesicles. Synaptic vesicles indeed belong to functionally distinct pools, but the molecular basis for these pools has remained unknown.

            In contrast to small synaptic vesicles that release classical neurotransmitters, large dense core vesicles release peptide hormones (e.g., insulin), neural peptides and growth factors (e.g., brain-derived neurotrophic factor).  However, the mechanism by which these peptides sort to a secretory pathway capable of regulated release remains a central question in cell biology.  We are therefore studying the formation of dense core vesicles and in particular, the recruitment of membrane proteins required for their regulated exocytosis.   We have identified some of the first components of the cytosolic machinery involved, and are now characterizing their roles.

            The presynaptic protein alpha-synuclein has a causative role in Parkinson’s disease and contributes to essentially all forms of the disorder.  However, the function of synuclein at the nerve terminal remains poorly understood.  We have recently found that it regulates the mode of exocytosis, and are now exploring the mechanism involved to understand how this influences neural degeneration. 

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

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

Students
Hongfei Xu
B.S., Qingdao University

Lab Manager
Samir Batarni
B.S., UC Davis

 

Lab Website

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