Neuroscience Graduate Program at UCSF
Vesicle Trafficking and Neurotransmitter Release
Brain processes underlying behavior, cognition, and emotion involve communication between neurons by the regulated release of neurotransmitter from synaptic vesicles. Synaptic vesicles reside in several functional pools in the presynaptic terminal that are defined by their location and probability of fusion upon stimulation. The high frequency of transmitter release observed at many synapses requires mechanisms to recycle synaptic vesicle membrane, proteins, and transmitter locally at the nerve terminal. Variation in the kinetics of vesicle recycling or mobilization from vesicle pools may shape the amount and pattern of neurotransmitter output, and hence contribute to information processing and some forms of synaptic plasticity. We are using a variety of complementary approaches—including biochemistry, live cell imaging, and mouse genetics—to understand how trafficking of synaptic vesicle components regulates synaptic transmission.
Multiple mechanisms have been proposed to mediate the recycling of synaptic vesicles, but most models assume that the protein components of the vesicles recycle together. However, specific sorting signals and protein interactions of the vesicular glutamate transporter, VGLUT1, direct recycling of this protein to different pathways. Comparison of VGLUT1 to other synaptic vesicle proteins reveals kinetic and mechanistic differences, indicating that the recycling of other proteins may be independently regulated. We are investigating the molecular mechanisms and regulation of individual synaptic vesicle protein recycling, which could result in activity-dependent alterations of synaptic vesicle (and plasma membrane) protein composition influencing transmitter release. These mechanisms may contribute to the different physiological properties observed at different types of synapses.
We demonstrated that VGLUT1 recycles in an activity-dependent manner to a novel pathway that uses the clathrin adaptor protein AP3 in addition to the well-described AP2 pathway. We are interested in the molecular mechanisms and functional consequences of targeting to different membrane trafficking pathways. The AP3 pathway may be particularly important in the recycling of synaptic vesicles from endosomes generated after prolonged stimulation, which may selectively replenish different vesicle pools. In addition, the endosomal pathway may be important in re-sorting proteins into functional synaptic vesicles or trafficking to a degradative pathway. Indeed, little is known about the lifetime and turnover of any synaptic vesicle protein. In the case of vesicular neurotransmitter transporters, protein levels could have significant effects on the amount of neurotransmitter stored and released.
We use and develop optical tools to image the dynamics of synaptic vesicle components. Fusions of vesicular neurotransmitter transporters with a pH-sensitive GFP will provide optical probes for imaging activity of neurotransmitter systems in individual neurons, circuits, and networks. These probes can be genetically encoded and targeted to specific neuronal populations, increasing the spatial resolution to study these systems. We are interested in studying the effect of drugs, treatments, or genes on neurotransmitter release in specific brain regions and circuits that may be relevant to neuropsychiatric disease. Our long term goal is to use these tools to gain insight into the pathophysiology of neuropsychiatric diseases and aid the development of novel therapeutics that alter synaptic transmission and behavior by altering neurotransmitter release.
See research summary
Sarah Foss, Graduate Student
Haiyan Li, Postdoctoral Fellow
Kevin Park, Lab Assistant
Magda Santos, Postdoctoral Fellow
Voglmaier SM, Edwards RH. Do different endocytic pathways make different synaptic vesicles?
Curr Opin Neurobiol. 2007 Jun;17(3):374-80.
Voglmaier SM, Kam K, Yang H, Fortin DL, Hua Z, Nicoll RA, Edwards RH. Distinct endocytic pathways control the rate and extent of synaptic vesicle protein recycling. Neuron 2006 Jul 6;51(1):71-84.
Fortin DL, Nemani, VM, Voglmaier SM, Anthony MD, Ryan TA, Edwards RH. Neural activity controls the synaptic accumulation of alpha-synuclein. J. Neurosci. 2005 Nov 23, 25(47): 10913-21.
Fremeau RT Jr., Voglmaier S, Seal RP, Edwards RH. VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci. 2004 Feb; 27(2): 98-103.
Huang CF, Voglmaier SM, Bembenek ME, Saiardi A, Snyder SH. Identification and purification of diphosphoinositol pentakisphosphate kinase, which synthesizes the inositol pyrophosphate bis(diphospho)inositol tetrakisphosphate. Biochemistry. 1998 Oct 20, 37(42): 14998-5004.
Brandon MA, Voglmaier S, Siddiqi AA. Molecular characterization of a Dictyostelium G-protein alpha-subunit required for development. Gene. 1997 Oct 24, 200(1-2): 99-105.
Voglmaier SM, Bembenek ME, Kaplin AI, Dorman G, Olszewski JD, Prestwich GD, Snyder SH. Purified inositol hexakisphosphate kinase is an ATP synthase: diphosphoinositol pentakisphosphate as a high-energy phosphate donor. Proc. Nat. Acad. Sci. 1996 93(9): 4305-10.
Kaplin AI, Ferris CD, Voglmaier SM, Snyder SH. Purified reconstituted inositol 1,4,5-trisphosphate receptors: thiol reagents act directly on receptor protein. J. Biol. Chem. 1994 269(46): 28972-8.
Voglmaier SM, Keen JH, Murphy JE, Ferris CD, Prestwich GD, Snyder SH, Theibert AB. Inositol hexakisphosphate receptor identified as the clathrin assembly protein AP-2. Biochem. Biophys. Res. Comm. 1992 187(1): 158-63.
Nye JS, Snowman AM, Voglmaier S, Snyder SH. High-affinity cannabinoid binding site: regulation by ions, ascorbic acid, and nucleotides. J. Neurochem. 1989 52(6): 1892-7.
Nye JS, Voglmaier S, Martenson RE, Snyder SH. Myelin basic protein is an endogenous inhibitor of the high-affinity cannabinoid binding site in brain. J. Neurochem. 1988 50(4): 1170-8.
Susan Voglmaier, M.D./Ph.D.
UCSF Box 0984-F
Langley Porter Psychiatric Institute
401 Parnassus Avenue, room A101/103
San Francisco, CA 94143