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 basic 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 identified three families of proteins responsible for this activity. Vesicular monoamine transport protects against a parkinsonian toxin, implicating this activity in neurodegeneration as well as behavior. Vesicular glutamate transport determines the quantal response to release of a single synaptic vesicle and exhibits both unusual allosteric regulation by Cl- and H+ and an associated Cl- conductance. We use a combination of biochemical, structural and physiological methods to determine the mechanisms responsible and elucidate their role in neurotransmission.
The localization of vesicle transporters also defines the membranes capable of regulated release. Using them, we found that multiple neuronal populations release two classical neurotransmitters. Recently, we also found that individual neurons release the two transmitters with different properties, indicating storage in different synaptic vesicles and enabling them to extract different information from neural firing. 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.
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 mechanisms that regulate their release and their assembly remain major questions. 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,, from diabetes to psychiatric disease.
Pursuing the role of neurotransmitter release in Parkinson’s disease (PD), we also study 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. Recently, we found that it influences behavior of the fusion pore formed during regulated exocytosis. We now use a combination of live imaging and molecular biology to explore the mechanisms responsible and their role in degeneration.
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
Fei Li
Ph.D., Michigan State University
James Maas
M.D., Ph.D., Washington University
Gautam Runwal
Ph.D., Cambridge University
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