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Synaptic Structure and Plasticity 
Our lab focuses on postsynaptic processing at glutamate synapses in brain.
Plasticity at glutamate synapses underlies aspects of learning and memory
whereas disregulation of glutamate release is implicated in a variety
of neurodegenerative diseases including stroke and amyotrophic lateral
sclerosis. Transmission at these excitatory synapses is mediated primarily
by glutamate acting on two classes of ligand gated ion channels: AMPA
receptors and NMDA receptors.
A key breakthrough in understanding mechanisms for synapse assembly came
from the discovery that proteins containing PDZ motifs play central roles
in scaffolding receptors and signaling elements. The prototypical PDZ
protein, PSD-95, associates with NMDA receptors and a downstream effector
neuronal, nitric oxide synthase (nNOS). We are using cellular, structural
and physiological approaches to understand how the regulatory domains
of PSD-95, which include an SH3 domain, a guanylate kinase domain, and
sites for N-terminal palmitoylation mediate synaptic plasticity.
The first transmembrane protein found to interact with glutamate receptors
is stargazin. Working together with Dr. Roger Nicoll's group, we found
that stargazer mutant mice lack synaptic AMPA responses due to a block
in AMPA receptor trafficking. Some of our current work focuses on how
stargazin promotes delivery of AMPA receptors to the plasma membrane and
on how stargazin regulates the synaptic cycling of AMPA receptors that
underlies synaptic plasticity.
Selected Publications:
Hillier-B-J. Christopherson-K-S. Prehoda-K-E. Bredt-D-S. and Lim-W-A.
Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS-syntrophin
complex Science 1999 284: 812-815.
El-Husseini-A-E. Schnell-E. Chetkovich-D-M. Nicoll-R-A. and Bredt-D-S.
PSD-95 Drives Maturation of Excitatory Synapses Science 2000 290: 1364-1368.
Chen-L. Chetkovich-D-M. Petralia-R-S. Sweeney-N. Kawaski-Y. Wenthold-R-J.
Bredt-D-S. and Nicoll-R-A. Stargazin regulates the synaptic targeting
of AMPA receptors by two distinct mechanisms Nature 2000 408: 936-943
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Contact Information:
Email: bredt@itsa.ucsf.edu
Phone: (415)-476-6310
Address: Box 0444, Room S 859
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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