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Gary Westbrook received an M.D. from Case Western Reserve University in 1976 after undergraduate work in Biology and graduate study in Biomedical Engineering. He was an intern and resident at Mt. Auburn Hospital in Boston and at the Washington University School of Medicine in St. Louis. After clinical training in Internal Medicine and Neurology, he spent six years at the National Institutes of Health before moving to the Vollum Institute in 1987. He is a senior scientist and holds concurrent appointments in Neurology and in Physiology and Pharmacology in the School of Medicine.
Research Interests
Synapses move information around the nervous system, and their dysfunction has been increasingly recognized as a factor in many neurological diseases. The goal of the Westbrook lab is to understand synaptic transmission in the central nervous system. They use electrical and optical recording methods to examine excitatory synapses that use L-glutamate as their neurotransmitter, or inhibitory synapses that use gamma-aminobutyric acid (GABA). These synapses mediate the majority of rapid information transfer in the brain. Experiments are directed at several levels, from regulation and localization of individual receptors to the behavior of single synapses, and the mechanisms by which small networks of synapses shape sensory information.
At the receptor level, the lab has explored the functional interaction between glutamate receptors and signaling molecules at the postsynaptic density. Molecular and physiological methods are used to explore the role of specific NMDA receptor subunits and interacting proteins during synapse formation. For example, Westbrook and coworkers have found that there is a matching of presynaptic and postsynaptic characteristics at developing hippocampal synapses. This maturation appears to be activity-dependent and depends on a specific cell adhesion molecule, a beta3-containing integrin. These results reinforce the idea that the synapse is a highly specialized cell-cell contact whose organization depends on molecules that coordinate pre- and postsynaptic properties.
At the level of single synapses, the lab has examined how distinctive kinetic features of glutamate and GABA receptors shape the overall neuronal response to synaptic activation. These studies utilize novel methods to measure the time course of inhibitory transmitter in the synaptic cleft. Their results suggest that closely spaced synapses can interact because transmitter spills out of one synapse and binds to receptors at adjacent synapses. Westbrook and colleagues are also examining the incorporation of newborn neurons into the synaptic network of the hippocampus using a unique transgenic mouse in which newborn dentate granule cells are marked with EGFP under control of the proopiomelanocortin promoter. Their results suggest that development of dendrites and formation of synapses is delayed due to the local environment of the adult hippocampus. They are using these mice to examine the functional and morphological development of new synapses, as well as the molecules that control dendritic development.
At the level of synaptic networks, the Westbrook group uses the olfactory bulb as a model circuit. They are interested in understanding how the unique synaptic architecture of the bulb shapes the highly organized incoming sensory information. Their current experiments focus on a set of 1000 neuropil structures in the olfactory bulb called glomeruli. Neurons within a glomerulus receive specific sensory input and show highly synchronized activity. Their experiments have revealed both slow and fast coordination of activity in glomeruli involving slow modulatory receptors such as metabotropic glutamate receptor 1, as well as rapid action potential synchronization involving the gap junction molecule, connexin 36, on distal dendrites. These studies provide a basis for probing the mechanisms for detection and discrimination in this sensory system.
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Selected Publications
Overstreet, L.S., Hentges, S.T., Bumaschny, V.F., de Souza, F.S.J., Smart, J.L., Santangelo, A.M., Low, M.J., Westbrook, G.L., and Rubinstein, M., (2004) A transgenic marker for newly born granule cells in dentate gyrus. J. Neurosci. 24:3251-3259.
Overstreet, L.S. and Westbrook, G.L. (2003) Synaptic density regulates independence at unitary inhibitory synapses. J. Neurosci. 23:2618-2626.
Schoppa, N.E. and Westbrook, G.L. (2002) AMPA autoreceptors drive correlated spiking in olfactory bulb glomeruli. Nature Neurosci. 5:1194-1202.
Tovar, K.R. and Westbrook, G.L. (2002) Mobile NMDA receptors at a hippocampal synapse. Neuron 34:255-264.
Chavis, P. and Westbrook, G. (2001) Integrin-directed maturation of presynaptic and postsynaptic compartments at a hippocampal synapse. Nature 411:317-321.
Krupp, J.J., Vissel, B., Heinemann, S.F., and Westbrook, G.L. (2001) A use-dependent tyrosine dephosphorylation modulates NMDA receptors independent of ion influx. Nature Neurosci. 4:587-596.
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