Robert Edwards, MD

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 many 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 have identified three distinct families of proteins responsible for this activity.  Vesicular monoamine transport protects against a parkinsonian toxin, implicating this activity in neurodegeneration as well as neuromodulation and behavior.  Vesicular glutamate transport determines the quantal response to release of a single synaptic vesicle and the physiological role of its complex allosteric regulation remains poorly understood. Localization of these transporters also defines the membranes capable of regulated release.  Using them, we have been able to demonstrate that multiple neuronal populations release two classical neurotransmitters.  The function of corelease remains unclear, but we have found that the two transmitters can influence each others packaging, and also act as independent signals.  Indeed, synaptic vesicles belong to functionally distinct pools, and we are using the vesicular transporters to elucidate their properties and origin, with important implications for development as well as neurotransmission.

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 mechanism by which they acquire the capacity for regulated exocytosis 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 using them to explore this process central to organismal physiology. 

Pursuing the role of neurotransmitter release in Parkinson’s disease (PD), we are also studying the role of 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.  We have now found that it influences behavior of the fusion pore formed during regulated exocytosis.  We now wish to understand the mechanism responsible and its role in degeneration.

Lab members:

Postdoctoral Fellows
Jacob Bendor
Ph.D., Rockefeller

Jacob Eriksen
Ph.D., University of Copenhagen

Ignacio Ibanez
Ph.D., Universidad Autonoma de Madrid

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

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