Robert Edwards, MD

Department of Neurology and Physiology
+1 415 502-5687
Research Overview: 

The Synaptic Basis of Behavior and Neuropsychiatric Disease

The nervous system encodes information through the timing and frequency of action potentials. Synapses process this input by determining which features of the firing pattern release neurotransmitter. However, we do not understand the molecular mechanisms responsible for extracting this information, making it difficult to understand the function of neural circuits, their role in behavior and their dysfunction in neuropsychiatric disease.

We work on several, fundamental questions about the regulation of neurotransmitter release and its consequences for physiology, behavior and disease.

1) What is the normal function of proteins involved in neurodegeneration? Neural degeneration is associated with the aggregation of characteristic proteins such as a-synuclein (in the case of Parkinson’s disease). We know very little about the normal function of these proteins even though that is the context in which disease originates. Parkinson’s disease involves a dopamine deficiency and synuclein is a presynaptic protein that can inhibit release. We thus wish to understand how the function of synuclein contributes to both symptoms and the underlying degenerative process.

2) What targets peptides for regulated release? Dense core vesicles mediate the release of peptide hormones and neural peptides. The properties of release dictate the time course of signaling and in pancreatic isleet cells, defects underlie type 2 diabetes. However, we know very little about the formation of dense core vesicles and how they acquire the membrane proteins that determine the speed and mode of fusion. We have identified several components of the machinery required for biogenesis of dense core vesicles. We now wish to understand how they function to assemble dense core vesicles and the physiological consequences for release.

3) What tunes neurotransmitter release to different firing frequencies? The high speed of neurotransmitter release enables many synapses to convey precise information about timing, but the resulting depletion of synaptic vesicles limits the response to firing at high frequency. In contrast, burst firing triggers the phasic dopamine release required for reinforcement learning. What determines the role of a synapse in extracting information about timing versus frequency? The analysis of neurotransmitter corelease has begun to suggest the cellular mechanisms responsible for these two modes of signaling, and we wish to explore the consequences for neural circuitry and behavior.

4) How do synaptic vesicles fill with neurotransmitter? The quantal nature of neurotransmission depends on the regulated exocytosis of synaptic vesicles filled with transmitter. We have identified several of the proteins that transport neurotransmitters into synaptic vesicles and wish to understand how they coordinate this activity with the rapidly changing conditions that accompany the exo- and endocytic cycling of synaptic vesicles. We combine structural approaches with biochemistry, imaging and synaptic physiology to understand how the mechanism and regulation of vesicular glutamate transport influences neurotransmission, circuits and neurological disease.

Lab members:

Postdoctoral Fellows

Poulomi Das
Ph.D., Nanyang Technical University, Singapore

Ignacio Ibanez
Ph.D., University of Barcelona

Shweta Jain
Ph.D., National Centre for Biological Sciences, Bangalore

Christiana Kontaxi
Ph.D., University of Edinburgh

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

Akio Mori
M.D., Ph.D., Juntendo University

Gautam Runwal
Ph.D., Cambridge University

Hongfei Xu
Ph.D., Qingdao University

Pengcheng Zhang
Ph.D., UC Berkeley

Lab Manager
Sarah Gierok

Primary Thematic Area: 
Secondary Thematic Area: 
Research Summary: 
The Molecular Basis of Neurotransmitter Release and Its Role in Synaptic Physiology, Behavior and Disease
Mentorship Development: 

9/11/20    Mentoring Across Differences


Featured Publications: 

SNX5 targets a monoamine transporter to the TGN for assembly into dense core vesicles by AP-3.

The Journal of cell biology

Xu H, Chang F, Jain S, Heller BA, Han X, Liu Y, Edwards RH

Ion transport and regulation in a synaptic vesicle glutamate transporter.

Science (New York, N.Y.)

Li F, Eriksen J, Finer-Moore J, Chang R, Nguyen P, Bowen A, Myasnikov A, Yu Z, Bulkley D, Cheng Y, Edwards RH, Stroud RM

Structures suggest a mechanism for energy coupling by a family of organic anion transporters.

PLoS biology

Leano JB, Batarni S, Eriksen J, Juge N, Pak JE, Kimura-Someya T, Robles-Colmenares Y, Moriyama Y, Stroud RM, Edwards RH

Synaptic Vesicle Recycling Pathway Determines Neurotransmitter Content and Release Properties.


Silm K, Yang J, Marcott PF, Asensio CS, Eriksen J, Guthrie DA, Newman AH, Ford CP, 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

a-Synuclein promotes dilation of the exocytotic fusion pore.

Nature neuroscience

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

Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.


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

Efficient, complete deletion of synaptic proteins using CRISPR.


Incontro S, Asensio CS, Edwards RH, Nicoll RA

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

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

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

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

v-SNARE composition distinguishes synaptic vesicle pools.


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

Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate.

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

Stuber GD, Hnasko TS, Britt JP, Edwards RH, Bonci A

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

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


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

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


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

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


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

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


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

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


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

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