Robert Edwards, MD

Professor
Department of Neurology
+1 415 502-5687

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

Primary Thematic Area: 
Neurobiology
Secondary Thematic Area: 
None
Research Summary: 
The Molecular Basis of Neurotransmitter Release and Its Role in Synaptic Physiology, Behavior and Disease

Websites

Featured Publications: 

Neural activity controls the synaptic accumulation of alpha-synuclein.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Fortin DL, Nemani VM, Voglmaier SM, Anthony MD, Ryan TA, Edwards RH

Distinct endocytic pathways control the rate and extent of synaptic vesicle protein recycling.

Neuron

Voglmaier SM, Kam K, Yang H, Fortin DL, Hua Z, Nicoll RA, Edwards RH

Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.

Neuron

Seal RP, Akil O, Yi E, Weber CM, Grant L, Yoo J, Clause A, Kandler K, Noebels JL, Glowatzki E, Lustig LR, Edwards RH

Optical reporters for the conformation of alpha-synuclein reveal a specific interaction with mitochondria.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Nakamura K, Nemani VM, Wallender EK, Kaehlcke K, Ott M, Edwards RH

Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors.

Nature

Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH

Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis.

Neuron

Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH

Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo.

Neuron

Hnasko TS, Chuhma N, Zhang H, Goh GY, Sulzer D, Palmiter RD, Rayport S, Edwards RH

Vesicular monoamine and glutamate transporters select distinct synaptic vesicle recycling pathways.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Onoa B, Li H, Gagnon-Bartsch JA, Elias LA, Edwards RH

Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein.

The Journal of biological chemistry

Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K, Munishkina L, Zhang J, Gardner B, Wakabayashi J, Sesaki H, Cheng Y, Finkbeiner S, Nussbaum RL, Masliah E, Edwards RH

v-SNARE composition distinguishes synaptic vesicle pools.

Neuron

Hua Z, Leal-Ortiz S, Foss SM, Waites CL, Garner CC, Voglmaier SM, Edwards RH

Presynaptic regulation of quantal size: K+/H+ exchange stimulates vesicular glutamate transport.

Nature neuroscience

Goh GY, Huang H, Ullman J, Borre L, Hnasko TS, Trussell LO, Edwards RH

Ventral tegmental area glutamate neurons: electrophysiological properties and projections.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Hnasko TS, Hjelmstad GO, Fields HL, Edwards RH

Multiple dileucine-like motifs direct VGLUT1 trafficking.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Foss SM, Li H, Santos MS, Edwards RH, Voglmaier SM

Self-assembly of VPS41 promotes sorting required for biogenesis of the regulated secretory pathway.

Developmental cell

Asensio CS, Sirkis DW, Maas JW, Egami K, To TL, Brodsky FM, Shu X, Cheng Y, Edwards RH

Efficient, complete deletion of synaptic proteins using CRISPR.

Neuron

Incontro S, Asensio CS, Edwards RH, Nicoll RA

Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.

Neuron

Eriksen J, Chang R, McGregor M, Silm K, Suzuki T, Edwards RH

Endogenous Leucine-Rich Repeat Kinase 2 Slows Synaptic Vesicle Recycling in Striatal Neurons.

Frontiers in synaptic neuroscience

Maas JW, Yang J, Edwards RH

a-Synuclein promotes dilation of the exocytotic fusion pore.

Nature neuroscience

Logan T, Bendor J, Toupin C, Thorn K, Edwards RH

A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry.

Nature communications

Ullman JC, Yang J, Sullivan M, Bendor J, Levy J, Pham E, Silm K, Seifikar H, Sohal VS, Nicoll RA, Edwards RH