Robert Edwards, MD

Professor
Neurology
415-502-5687

The Synaptic Basis of Behavior

            Information processing by the nervous system occurs at synapses, where chemical neurotransmitter transduces an electrical signal between neurons. The properties of neurotransmitter release determine the information extracted from neural firing, such as about timing or frequency. However, the mechanisms responsible and their physiological role in neural circuits and behavior remain poorly understood but fundamental aspects of neural function.  These processes also contribute to diseases of the nervous system, and we wish to understand how. 

            The exocytosis of a single synaptic vesicle produces a postsynaptic response (quantum) that is considered the elementary unit of synaptic transmission, but the factors that determine the amount of neurotransmitter per vesicle remain poorly understood. With the vesicular neurotransmitter transporters as a starting point, we use a combination of biochemical, structural and physiological approaches to understand the cellular mechanisms involved and determine their role in synaptic transmission.  We are particularly interested in the allosteric regulation of vesicular glutamate transport by Cl-, H+ and an associated Cl- conductance. 

            It has become increasingly clear that many neurons release two classical neurotransmitters, in addition to neural peptides. Since the localization of vesicular neurotransmitter transporters defines the vesicles capable of regulated release, we have used them to study corelease. The results show that although different transmitters can be stored in the same vesicle, they can also be released with different properties, reflecting storage in vesicles that differ in the properties of release and hence extract different information from neural firing. We focus on glutamate corelease by dopamine neurons and find glutamate release sensitive to timing, dopamine release to firing frequency. 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.

            Neuromodulators such as neural peptides subserve roles in neurotransmission distinct from classical transmitters like glutamate and GABA. To understand their regulation and role in behavior, we study the exocytosis and formation of peptidergic large dense core vesicles (LDCVs). 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.

            The presynaptic locus of Parkinson’s disease has implicated neurotransmitter release in pathogenesis of the underlying degeneration.   We originally identified the vesicular monoamine transporter by virtue of its ability to protect against a parkinsonian toxin.  In addition, the presynaptic protein alpha-synuclein has a causative role in Parkinson’s.  Like many other proteins central to neurodegeneration, however, its normal function has remained unknown.  We have recently identified the normal function of synuclein and are using an assay for this activity to understand its role in physiology and disease. 

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, India

Fei Li
Ph.D., Michigan State University

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

Gautam Runwal
Ph.D., Cambridge Univesity

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

 

Lab Website

 

Academic community service and committee membership: NS admissions committee, Chair of NS student advisors/student progress committee

Publications: