Structure of the Synapse


Dr. Charles Stevens

Dr. Charles Stevens is Professor in the Molecular Neurobiology Department at the Salk Institute and is an Investigator of the Howard Hughes Medical Institute. Dr. Stevens' research centers on mechanisms responsible for synaptic transmission. These problems are approached by a combination of molecular biological, electrophysiological, anatomical, and theoretical methods. His laboratory studies neurons both in dissociated cell culture and in brain slices, and also investigates the function of individual membrane proteins of importance for synaptic transmission. One main current research focus is the various mechanisms used by the central nervous system for the short- and long-term regulation of synaptic strength. A second principal project uses a combination of methods to elucidate the molecular basis to neurotransmitter release at synapses.

Virtually all of the circuits in the vertebrate brain posses what computer scientists call a scalable architecture. What this means is that the computational power of vertebrate neural circuits can be increased by simply making them larger while conforming to a single basic design. The vast majority of computers currently in use have what is known as a von Neumann architecture, one that is not scalable, but brains must use a scalable architecture in order for evolution to work. Starting with quantitative neuroanatomical, physiological, and molecular biological data, Dr. Stevens' laboratory uses theoretical methods to learn the design principles that endow vertebrate neural circuits with a scalable architecture.

Dr. Reinhard Jahn

Dr. Reinhard Jahn is the Director of the Department of Neurobiology at the Max-Planck-Institut für Biophysikalische Chemiein in Gottingen , Germany. Since his postdoctoral years with Paul Greengard in the early eighties, the research interests of Reinhard Jahn have focussed on the molecular mechanisms of neuronal exocytosis and synaptic vesicle cycling. Using purified synaptic vesicles to characterize proteins involved in the synaptic vesicle cycle, his work contributed to the discovery of the proteins involved in membrane fusion (SNAREs), in synaptic Ca2+-signalling (synaptotagmins), and in neurotransmitter uptake and storage. More recently, he has worked on the mechanism of SNARE assembly and SNARE-mediated membrane fusion, leading to the "zippering hypothesis". In addition, his lab has recently carried out a comprehensive and quantitative description of the macromolecular composition of synaptic vesicle, leading to the development of a first structural model of a trafficking organelle.

Eukaryotic cells are compartmentalized into membrane-bound organelles. Membrane-impermeant macromolecules are transported from one compartment to another, and in and out of cells, without compromising membrane integrity. Furthermore, organelles need to be generated continuously during growth. To achieve these goals, elaborate mechanisms evolved for budding, splitting, and fusion of organelles and of whole cells without leakage of intra-organellar content or disturbance of the asymmetry of the surrounding membranes. We are mainly interested in the molecular mechanisms of membrane fusion with a focus on exocytosis of synaptic vesicles and fusion of endosomes. In recent years it has become clear that most, and perhaps all, intracellular membrane fusion events are mediated by sets of evolutionarily conserved membrane proteins. Among these, the SNARE proteins are the best candidates for catalyzing the fusion reaction. SNARE proteins are abundant on intracellular membranes and readily form stable complexes. It is currently thought that these proteins operate as "nanomachines" which force the membranes together and thus initiate membrane fusion. SNARE proteins interact with a long and still growing list of other proteins that regulate their conformation and control their availability for the fusion reaction. We study membrane fusion using a variety of complementary experimental approaches. They include an analysis of SNAREs and SNARE-interacting proteins with biochemical and biophysical techniques, correlation of structure with function of SNAREs in yeast, study of vesicle fusion using native and artificial membranes, characterization of how exo- and endocytotic sites at the plasma membrane are organized, and measurement of exocytosis with electrophysiological methods. Furthermore, we are interested to find out how neurotransmitters are sequestered and stored in synaptic vesicles

Dr. Axel Brunger

Dr. Axel Brunger is Professor of Molecular and Cellular Physiology at Stanford University and is an Investigator of the Howard Hughes Medical Institute. The goal of his laboratory is to understand the molecular mechanism of synaptic neurotransmission. The lab is interested in the structure, function, and dynamics of key players in the synaptic vesicle fusion machinery. Further work is being conducted on the mechanism of action of clostridial neurotoxins that target this machinery. Other projects include protein complexes that are involved in synaptic development and the ATPases of the AAA family that are involved in protein complex disassembly and degradation. A molecular understanding of these complex protein machineries may ultimately lead to new therapeutics to treat human diseases. The approach that the Brunger lab takes to understanding the molecular basis for neurotransmission consists of a combination of structural, functional, and dynamics studies. Structural information about the most important complexes between the individual molecular components is first obtained by x-ray crystallography, electron microscopy, or nuclear magnetic resonance spectroscopy. This information provides the framework for investigations targeted at the functional and dynamic aspects of the system, using single-molecule microscopy and spectroscopy techniques.

Dr. Eric Gouaux

Dr. Eric Gouaux is a Senior Scientist at the Vollum Institute and an Investigator of the Howard Hughes Medical Institute. Dr. Gouaux completed his A.B. and Ph.D. degrees in Chemistry at Harvard University in 1989, and pursued his postdoctoral studies at Harvard and at the Massachusetts Institute of Technology. In 1993, he was appointed assistant professor at the University of Chicago Department of Biochemistry and Molecular Biology. In 1996, he joined the Department of Biochemistry and Molecular Biology at Columbia University. While there, in 2000, he was appointed Investigator with the Howard Hughes Medical Institute. He moved to Oregon Health & Science University in 2005 as a Senior Scientist at the Vollum Institute, continuing his position with Howard Hughes. The work in the Gouaux Lab is concentrated on developing molecular mechanisms for the function of receptors and transporters at chemical synapses. Glutamate, glycine and the biogenic amines are neurotransmitters of particular significance, and currently the lab is focusing its efforts on eukaryotic glutamate receptors and on bacterial homologs of the transporters for glutamate, glycine and the biogenic amines. While the lab's primary tool is x-ray crystallography, they also utilize electrophysiology as well as other biophysical and biochemical methods. Dr. Gouaux's laboratory has made landmark studies of membrane proteins that play central roles in synaptic transmission, including publishing the first structures of a pore-forming toxin, #-hemolysin, in its membrane-bound heptameric and water-soluble monomeric states; solving the first structure of a glutamate-receptor ligand-binding domain from the GluR2 receptor, as well as the first structures of NMDA receptor glycine and glutamate binding domains; defining the first structures of sodium-dependent transport proteins for aspartate (GltPh) and leucine (LeuT), orthologs of the human glutamate and biogenic amine neurotransmitter transporters; and publishing the first crystal structure of an acid sensing ion channel, thus determining the stoichiometry and architecture of this family of receptor and illuminating the fundamental structural features of the closely related epithelial sodium channels.

Dr. Nigel Unwin (The Severo Ochoa Lecture)

Dr. Nigen Unwin is Head of Neurobiology Division, MRC Laboratory of Molecular Biology at Cambridge University. Dr. Unwin obtained his PhD in metallurgy at the University of Cambridge, and then took a position at the MRC Laboratory of Molecular Biology in Cambridge (LMB). He left LMB in 1980 to become Professor of Cell Biology at Stanford University School of Medicine, but returned in 1988. In 1992 he became Head of the Neurobiology Division. Nigel is interested in developing electron microscopical methods and using them to analyse the structures of membrane proteins. In 1975, together with Richard Henderson, he determined the first structure of an integral membrane protein: bacteriorhodopsin. More recently, his research has focused on the structure of the acetylcholine receptor - a neurotransmitter-gated ion channel - and how it responds to acetycholine released into the synaptic cleft. He obtained an atomic model of this ion channel in 2005.

Dr. Morgan Sheng

Morgan Sheng is the Menicon Professor of Neuroscience at the Massachusetts Institute of Technology (MIT; currently on leave of absence). He was Investigator of the Howard Hughes Medical Institute until Sept 2008 when he took on the job of Vice President, Neuroscience, at Genentech Inc, South San Francisco. Dr. Sheng received his B.A. in Physiology from Oxford University, UK, and his medical degree (MBBS) from London University, UK. After 4 years of residency in internal medicine, he switched to basic research in molecular biology, obtaining a PhD from Harvard Medical School in the lab of Michael Greenberg. He pursued postdoctoral training in the lab of Lily Jan at UCSF. From 1994 to 2001, Morgan Sheng was on the faculty of the Department of Neurobiology, Massachusetts General Hospital and Harvard Medical School. He joined MIT in 2001.

Dr. Sheng's lab has made major contributions to the understanding of the molecular organization of excitatory synapses (particularly the postsynaptic density), signaling and receptor trafficking mechanisms that underlie synaptic plasticity, and the structure and regulation of dendritic spines. He is presently interested in how defects in synaptic structure and function might give rise to neurological disease and mental illness.

Dr. Robert C. Malenka

Dr. Robert C. Malenka is the Pritzker Professor of Psychiatry and Behavioral Sciences, Director of the Pritzker Laboratory, and co-director of the Stanford Institute for Neuro-Innovation and Translational Neurosciences at the Stanford University School of Medicine. He has been a world leader in elucidating the mechanisms underlying the action of neurotransmitters in the mammalian brain and the molecular mechanisms by which neural circuits are reorganized by experience. His many contributions over the last 25 years have laid the groundwork for a much more sophisticated understanding of the mechanisms by which neurons communicate and the adaptations in synaptic communication which underlie all forms of normal and pathological behavior. He was trained as both a clinical psychiatrist and cellular neurobiologist and has been at the forefront of helping to apply the knowledge gained from basic neuroscience research to the treatment and prevention of major neuropsychiatric disorders. He is an elected member of the Institute of Medicine of the National Academy of Sciences (2004) and an elected fellow of the American Academy of Arts and Sciences (2005) and the American Association for the Advancement of Science (2009). His public service includes serving on the National Advisory Council on Drug Abuse and as a Councilor for the Society for Neuroscience. He is the co-author of the textbook Molecular Neuropharmacology: A Foundation for Clinical Neuroscience and has served on the editorial boards of many prominent journals including Neuron, Trends in Neuroscience, Biological Psychiatry and the American Journal of Psychiatry.

The 2009 Skirball Institute Eleventh Annual Symposium is organized by Da-Neng Wang and Stevan Hubbard.

Direct all inquiries to Laura Rivera.