Gary Westbrook, M.D.

Gary Westbrook, MD

Senior Scientist, Vollum Institute

Rocky and Julie Dixon Professor of Neurology

Email: westbroo@ohsu.edu
Phone: 503-494-5429
Office: Vollum 2431A
Westbrook Lab
View research papers on PubMed

Biography

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

Most of the current work in our lab focuses on the mouse entorhinal-dentate circuit that is the entry pathway for information arriving in the hippocampus. Our main interest is how synapses are formed and regulated. This circuit has a number of technical advantages as well as significant implications for memory formation, and it is one of the first brain regions to undergo deterioration in Alzheimer’s disease. What are these experimental advantages? Well firstly the inputs to the dentate gyrus are anatomically parsed between inputs carrying contextual information coming from the lateral entorhinal cortex and spatial information coming from the medial entorhinal cortex. These inputs in the perforant path form synapses on different parts of the dendritic arbors of dentate granule cells, and thus can be easily separated experimentally. These pathways differentially signal the “what, when and where” of information entering the hippocampus. The dentate granule cells also can be subdivided into mature granule cells and a population of adult-born granule cells (“newborn neurons”) that are constantly integrating into the mature circuitry. This circuit design is obviously important to its function, but also allows us to differentially manipulate these elements to understand circuit function.

We started this work a number of years ago 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 indicated that development of dendrites and formation of synapses is delayed due to the local environment of the adult hippocampus. We used these and other mice to examine the functional and morphological development of new synapses, as well as the molecules that control the development of dendrites and synapses. 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. We use 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 as well as electrophysiological recording in acute brain slices.

Recently we have focused on how neural activity can re-shape synaptic circuitry of both inputs and both types of dentate granule cells. Our work has shown that newborn neurons preferentially receive “contextual” input from the lateral entorhinal cortex (Woods et al., 2018). To understand how neural activity alters gene expression in this circuit, we have used exercise as a physiological stimulus to induce activity in the dentate gyrus and then track gene expression in “exercise–activated” cells using a transgenic mouse in which the immediate early gene c-fos promoter is hooked to a fluorescent reporter to permanently tag cells activated by a single bout of exercise. These experiments, a collaboration with the lab of Richard Goodman, led us to the discovery of an activity-dependent gene that we think serves as an early effector of dendritic spine formation in dentate granule cells (Chatzi et al., 2019). We are using a combination of approaches to pursue this project including genetic, morphological, functional (electrophysiology) and behavioral strategies.

A new project on anti-NMDA receptor encephalitis is also underway in the lab and is described on our projects page (Jones et al., 2019).

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.

Vaaga CE, Westbrook GL. (2016) Parallel processing of afferent olfactory sensory information. J. Physiol. 594:6715-6732.

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

Tovar KR, McGinley MJ, Westbrook GL. (2013) Triheteromeric NMDA receptors at hippocampal synapses. J. Neurosci. 33:9150-9160.

Overstreet-Wadiche LS, Bromberg DA, Bensen AL, Westbrook GL. (2006) Seizures accelerate functional integration of adult-generated granule cells. J. Neurosci. 26:4095-4103.

Tovar KR, Westbrook GL. (2002) Mobile NMDA receptors at hippocampal synapses. Neuron 34:255-264.

Chavis P, Westbrook G. (2001) Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse. Nature 411:317-321.

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.

Schoppa NE, Kinzie JM, Sahara Y, Segerson TP, Westbrook GL. (1998) Dendrodendritic inhibition in the olfactory bulb is driven by NMDA receptors. J. Neurosci. 18:6790-6802.

Jones MV, Westbrook GL. (1995) Desensitized states prolong GABAA channel responses to brief agonist pulses. Neuron 15:181-191.

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.

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.

Lester RA, Clements JD, Westbrook GL, Jahr CE. (1990) Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature 346:565-567.

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.