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Helen Wills Neuroscience
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UC Berkeley
UC Berkeley MCB Department
Helen Wills Neuroscience Institute

Robert S. Zucker
Professor (Emeritus) of Neurobiology and Professor of the Graduate School
University of California, Berkeley
Department of Molecular and Cell Biology, Division of Neurobiology
Neuroscience Institute
Biophysics Graduate Program

Contact Information:
Professor Robert Zucker
University of California
Department of Molecular and Cell Biology
111 Life Sciences Addition
Berkeley, CA 94720-3200 USA
Office Phone: (510) 642-3407
Fax Line: (510) 642-3407, or 643-6791
E-Mail: zucker@berkeley.edu

Advising Hour during semesters (Open Office Hour): Wednesdays, 4:15-5:30 PM
     Exceptions (out of town): Aug. 31- Sep. 10, Sep. 22-25
     Available Monday, Sep. 21, 1:15-2:00 PM

Research Interests

Synapses are not static; they are highly regulated. The strength of synaptic transmission can wax and wane after a bout of activity, and this shapes the information processing properties of neural circuits. Our lab concentrates on studying the mechanisms regulating synaptic transmission.

We use biophysical methods such as control of second messengers by photolysis of light sensitive caged compounds, measurement of second messengers with fluorescent dyes, detection of molecular rearrangements using fluorescence resonance energy transfer (FRET), tracking of vesicle movements with vital vesicle membrane labeling dyes, and mathematical modeling and computational simulations, as well as electrophysiological techniques, to study the mechanisms underlying regulation of synaptic transmission.

Recent Projects

We study the roles of calcium in triggering transmitter release at fast synapses, and in modulating release following prior activity. Presynaptic calcium not only triggers exocytosis, but also facilitates release after a single action potential, and enhances release after a train of action potentials (post-tetanic potentiation, PTP), by binding to different target molecules in presynaptic terminals. Presynaptic mitochondrial loading and Na+ accumulation also play roles in PTP: the post-tetanic extrusion of Ca2+ by Na+/Ca2+ exchange is reversed, prolonging the enhancement of transmitter release by the lingering residual Ca2+ leaking out of mitochondria and in from the outside. Computer simulations of Ca2+ diffusion away from channel mouths to docked vesicles and facilitatory effectors can account for the time course of transmitter release, magnitude of facilitation, and measurements of presynaptic [Ca2+]. We are also exploring the rearrangements of presynaptic proteins triggered by Ca2+ using FRET. And we are exploring the Ca2+-dependence of transmitter release and short-term synaptic plasticity at neuromuscular junctions and cultured hippocampal synapses by photolysis of photosensitive Ca2+ chelators (caged Ca2+).

We have also studied forms of synaptic plasticity called long-term potentiation (LTP) and long-term depression (LTD), which are involved in memory consolidation in the mammalian brain. We have found that LTP is selectively triggered by short-lasting high [Ca2+]i elevations in hippocampal CA1 pyramidal neurons, while prolonged modest [Ca2+]i elevations selectively activate LTD. We have also explored a possible role for postsynaptic Ca2+ in CA3 pyramidal cells. Depolarization-induced suppression of inhibition (DSI) is another form of cortical synaptic plasticity, in which postsynaptic activity suppresses the release of transmitter from presynaptic inhibitory interneurons. We have shown that cortical DSI is caused by micromolar levels of [Ca2+] operating at a target distant from Ca2+ channel mouths.

At cholinergic synapses made by a multi-transmitter Aplysia neuron, Ca2+ acts quite locally, nonlinearly, and at high levels to secrete transmitter. In contrast, at peptidergic synapses from the same neuron, we have found that Ca2+ acts more linearly to release pre-docked vesicles located somewhat farther from Ca2+ channel mouths.

Serotonin is a neuromodulator of fast glutamatergic synapses, both in the brain and at crayfish neuromuscular junctions. Using membrane-labeling fluorescent dyes, we found that serotonin enhances transmission by increasing the pool of presynaptic vesicles available for release. We recently discovered that serotonin activates the production of cyclic AMP to activate a pathway involving exchange protein activated by cAMP (Epac) and to open presynaptic hyperpolarization and cyclic nucleotide-activated (HCN) channels to enhance secretion evoked by action potentials by an actin-dependent process.

Repetitive activity at crayfish neuromuscular junctions activates a long-term facilitation (LTF) of transmission. This process also depends on HCN channel activation. Na+ accumulates in nerve terminals, is extruded by an electrogenic Na+ pump whose hyperpolarization activates HCN channels to cause LTF. LTF also requires Ca2+ influx during stimulation, integrity of actin filaments, local presynaptic protein synthesis, the calcium-dependent dephosphorylation of a target protein, and the activity of numerous protein kinases that influence protein synthesis.

The docking and fusion of synaptic vesicles are functions of a complex of presynaptic proteins called SNAREs.  By labeling the SNARE proteins VAMP-2 and SNAP-25B with GFPs, we have been able to detect changes in fluorescence resonance energy transfer (FRET) that may report a tightening or reorientation of the SNARE complex on vesicle fusion as cis-SNAREs are formed, followed by disassembly of SNAREs after SNAREs have dispersed from the active zone but prior to endocytosis, and finally reassembly of SNAREs as new vesicles are docked and primed.

For more information on some of these projects, click here, or on the Projects button from any page.


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