Senior Scientist, Vollum Institute
Rocky and Julie Dixon Professor of Neurology
Dr. Westbrook received his medical training and did graduate study in Biomedical Engineering at Case Western Reserve University. He was then an intern and resident at Mt. Auburn Hospital in Boston (Internal Medicine) and at the Washington University School of Medicine in St. Louis (Neurology). After clinical training, he spent six years in basic neuroscience research at the National Institutes of Health before moving to the Vollum Institute in 1987. He is a senior scientist at the Vollum Institute and the Rocky and Julie Dixon Professor of Neurology in the School of Medicine. He served as co-director of the Vollum Institute from 2005–2016. Dr. Westbrook has been active in the development of the Jungers Center, a joint effort between the Vollum Institute and the Department of Neurology, as well as in OHSU training activities in disease-oriented neuroscience research. He initiated the Neurobiology of Disease course in the graduate program and served as the director of the Vollum/OHSU Neuroscience Graduate Program from 2008–2018. Dr. Westbrook has been the recipient of several research prizes, including a Jacob Javits Award and a Merit Award from the National Institutes of Health. He is a past editor-in-chief of the Journal of Neuroscience and now serves as a senior editor at eLife. He has served as a member of the Advisory Council of the National Institute of Neurological Diseases and Stroke (NINDS) and the NIH Council of Councils, which oversees the Common Fund.
Summary of current research
Synapses move information around the nervous system, and their dysfunction has been increasingly recognized as a factor in a wide range of neurodevelopmental disorders and neuropsychiatric diseases. The goal of the Westbrook lab is to understand normal and abnormal synaptic transmission in the central nervous system. We use electrical and optical recording as well as molecular methods to examine the formation, function, and plasticity of excitatory and inhibitory synapses. These synapses mediate the majority of rapid information transfer in the brain. Our experiments are directed at several levels, from regulation and localization of individual receptors to the behavior of single synapses, and to the mechanisms by which small networks of synapses regulate learning and memory and sensory processing. Our earlier work was mostly directed at the level of receptors, particularly N-methyl-D-aspartate receptors, and the function of single synapses. Our work has now largely shifted to studies of small networks or microcircuits in the hippocampus and olfactory system. Our goal is to understand how such circuits are formed, regulate their activity and contribute to the function of neural systems.
Most of the current work in our lab focuses on two projects. In the hippocampus, we are examining the incorporation of newborn neurons into the synaptic network of the hippocampus. We started this work using a unique transgenic mouse in which newborn dentate granule cells are marked with enhanced green fluorescent protein (EGFP) under control of the proopiomelanocortin promoter. Our results suggest that development of dendrites and formation of synapses is delayed due to the local environment of the adult hippocampus. We are using these and other mice to examine the functional and morphological development of new synapses, as well as the molecules that control dendritic development. We are using candidate gene approaches, unbiased genetic screens, as well as network perturbations to identify molecules that are critical to circuit formation. In order to study candidate genes, we use viral-mediated gene transfer in vivo, then assess the physiological behavior of synapses using imaging and electrophysiological recording in acute brain slices. We are also examining how the incorporation of newborn neurons is affected by seizures and brain injury. The integration of these newborn neurons provides a unique window into the formidable barriers to synaptogenesis, dendritic outgrowth and circuit formation in the adult nervous system. In terms of the potential for stem cells and cell replacement approaches, these barriers are perhaps more daunting than even cell differentiation and survival.
Jones BE, Tovar KR, Goehring A, Jalali-Yazdi F, Okada NJ, Gouaux E, Westbrook GL. (2019) Autoimmune receptor encephalitis in mice induced by active immunization with conformationally stabilized holoreceptors. Science Transl. Med. 11(500):eaaw0044.
Chatzi C, Zhang G, Hendricks WD, Chen Y, Schnell E, Goodman RH*, Westbrook GL*. (2019) Exercise-induced enhancement of synaptic function triggered by the inverse BAR protein, Mtss1L. Elife 8:e45920. *co-senior authors
Hendricks WD, Westbrook GL, Schnell E. (2019) Early detonation by sprouted mossy fibers enables aberrant dentate network activity. Proc. Natl. Acad. Sci. USA 116:10994-10999.
Woods NI, Vaaga CE, Chatzi C, Adelson JD, Collie MF, Perederiy JV, Tovar KR, Westbrook GL. (2018) Preferential targeting of lateral entorhinal inputs onto newly integrated granule cells. J. Neurosci. 38:5843-5853.
Wang S, Brunne B, Zhao S, Chai X, Li J, Lau J, Failla AV, Zobiak B, Sibbe M, Westbrook GL, Lutz D, Frotscher M. (2018) Trajectory analysis unveils Reelin's role in the directed migration of granule cells in the dentate gyrus.
J. Neurosci. 38:137-148.
Vaaga CE, Westbrook GL. (2017) Distinct temporal filters in mitral cells and external tufted cells of the olfactory bulb. J. Physiol. 595:6349-6362.
Hendricks WD, Chen Y, Bensen AL, Westbrook GL, Schnell E. (2017) Short-term depression of sprouted mossy fiber synapses from adult-born granule gells. J. Neurosci. 37:5722-5735.
Vaaga CE, Yorgason JT, Williams JT, Westbrook GL. (2017) Presynaptic gain control by endogenous cotransmission of dopamine and GABA in the olfactory bulb. J. Neurophysiol. 117:1163-1170.
Parent AS, Pinson A, Woods N, Chatzi C, Vaaga CE, Bensen A, Gérard A, Thome JP, Bourguignon JP, Westbrook GL. (2016) Early exposure to Aroclor 1254 in vivo disrupts the functional synaptic development of newborn hippocampal granule cells.
Eur. J. Neurosci. 44:3001-3010.
Tovar KR, Westbrook GL. (2017) Modulating synaptic NMDA receptors. Neuropharmacology 112(Pt A):29-33.
Schoppa NE, Westbrook GL. (2001) Glomerulus-specific synchronization of mitral cells in the olfactory bulb. Neuron 31:639-651.
Chavis P, Westbrook GL. (2001) Integrin-mediated maturation of presynaptic and postsynaptic compartments at a hippocampal synapse. Nature 411:317-321.
Jones MV, Westbrook GL. (1995) Desensitized states prolong GABAA channel responses to brief agonist pulses. Neuron 15:181-191.
Rosenmund C, Clements JD, Westbrook GL. (1993) Nonuniform probability of glutamate release at a hippocampal synapse. Science 262:764-767.
Clements JD, Lester RAJ, Tong G, Jahr CE, Westbrook GL. (1992) The time course of glutamate in the synaptic cleft. Science 258:1498-1501.
Tovar KR, Westbrook GL. (2002). Mobile NMDA receptors at hippocampal synapses. Neuron 34:255-264.
Tovar KR, Westbrook GL. (1999) The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J. Neurosci. 19:4180-4188.
Rosenmund C, Carr DW, Bergeson SE, Nilaver G, Scott JD, Westbrook GL. (1994) Anchoring of protein kinase A is required for modulation of AMPA/kainate receptors on hippocampal neurons. Nature 368:853-855.
MacDermott AB, Mayer ML, Westbrook GL, Smith SJ, Barker JL. (1986) NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321:519-522.
Mayer ML, Westbrook GL, Guthrie PB. (1984) Voltage dependent block by magnesium ions of NMDA responses in spinal cord neurones. Nature 309:261-263.