Professor, Neurobiology and Behavior
Director, Reeve-Irvine Research Center, Anatomy & Neurobiology
|Spinal cord injury, regeneration, sprouting, epilepsy, excitotoxicity, animal models of neurodegenerative diseases, synapse growth and plasticity, molecular mechanisms of LTP, LTD, and behavioral memory, mRNA localization, dendritic transport.|
|URL||Reeve-Irvine home page|
NIH Research Career Development Award, 1978-1983. Jacob Javitts Neuroscience Investigator Award, 1987-1994. Endowed Professorship: Harrison Foundation Professor of Neuroscience and Neurosurgery, 1990-1999.
Co-Recipient (with E.W. Rubel) OASI Institute International Award for Brain Dysfunction Research, 1991
NARSAD Distinguished Investigator Award, 1998, National Alliance for Research on Schizophrenia and Depression
Endowed Professorship: Reeve-Irvine Professor of Anatomy & Neurobiology and Neurobiology & Behavior. Member: Independent Citizen’s Oversight Committee (ICOC) for the Institute of Regenerative Medicine established by Proposition 71 (appointed by Governor Arnold Schwarzeneggar), 2004-2012.
Mechanisms of synapse growth and plasticity
Steward’s research program explores how neurons establish, maintain, and modify their synaptic connections. One component of my research evaluates cellular and molecular processes that contribute to repair after CNS (especially spinal cord) injury. A description of this component of my research may be found on the web site for the Reeve-Irvine Research Center. The second component addresses the mechanism underlying gene expression at synapses.
Information storage in the nervous system is thought to be mediated by changes in the strength of individual synapses. These changes in turn are determined by adjusting the structure and/or molecular composition of the synapse through a process that requires the expression of particular gene products. But how gene products are targeted to individual synapses, especially as individual synapses are being modified, still remains a mystery.
Almost 25 years ago, Steward discovered that polyribosomes were selectively localized just beneath postsynaptic membrane specializations on the dendrites of CNS neurons. Polyribosomes are collections of ribosomes that are actively engaged in synthesizing protein. They are the basic machinery of protein synthesis. Their localization at synapses immediately suggested what was then a novel idea about how neurons might manage the difficult task of synthesizing gene products for the thousands of individual synaptic sites that are present on a typical CNS neuron. Specifically, the localization of polyribosomes at synapses implied that certain key proteins that were important for the function of that individual synapse might be synthesized on site, and that this local synthesis might be controlled by signaling events at the individual synapse.
Steward’s current research assesses how particular mRNAs are targeted to individual synaptic sites on neuronal dendrites. We have shown that certain newly synthesized mRNAs are selectively targeted to synapses that had recently experienced a period of intense activity. The studies involve selective activation of a set of synapses that terminate in particular locations on the dendrites of neurons in the hippocampus. Strong activation of these synapses induces the expression of several immediate early genes, including one that encodes a protein known as Activity-regulated cytoskeleton-associated protein (Arc). In situ hybridization analyses revealed that newly synthesized Arc mRNA is selectively targeted to the postsynaptic domain of the synapses that had been activated. Our recent experiments have demonstrated that the signal for docking is triggered by NMDA receptor activation. We are now using a combination of molecular biological and neurophysiological techniques to further define the signal transduction events that cause newly synthesized mRNA to dock selectively at activated synapses.
Steward, O., and Schuman, E.M. (2003) Compartmentalized synthesis and degradation of proteins in neurons. Neuron, 40, Special Review Issue, "Cell Biology of the Neuron", 347-359.
McIntyre, C.K., Miyashita, T., Setlow, B., Marjon, K.D., Steward, O., Guzowski, J., and McGaugh, J.L. (2005). Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus. Proc. Nat. Acad. Sci., 102, 10718-10723.
Huang, F., Chotiner, J.K., and Steward, O. (2005) The mRNA for EF1alpha is localized in dendrites and translated in response to treatments that induce long-term depression (LTD). J. Neurosci. 25, 7199-7209.
Schuman, E.M, Dynes, J.L., and Steward, O. (2006) Synaptic regulation of translation of dendritic mRNAs. J. Neurosci.26, 7143-7146.
Huang, F., Chotiner, J.K., and Steward, O. (2007) Actin polymerization and ERK phosphorylation are required for Arc/Arg3.1 mRNA targeting to activated synaptic sites on dendrites. J. Neurosci., 27, 9054-9067.
Blanco, J.E., Anderson, K.D., and Steward, O. (2007) Recovery of forepaw gripping ability and reorganization of cortical motor control following cervical spinal cord injuries in mice. Exp. Neurol., 203, 333-348.
Dynes, J.L. and Steward, O. (2007) Dynamics of bi-directional transport of Arc mRNA in neuronal dendrites. J. Comp. Neurol., 500, 433-447.
Dynes, J., and Steward, O. (2008) Dendritic transport of mRNA, the IEG Arc, and synaptic modifications involved in memory consolidation. In: J. D. Sweatt (Ed.) Molecular Basis of memory, Vol. 4 of Learning and Memory: A comprehensive Reference, 4 vols. J. Byrne (Ed.), pp 587-610 Oxford, Elsevier.
Steward, O., Zheng, B., Tessier-Lavigne, M., Hofstadter, M., Sharp, K., Yee, K.M. (2008) Regenerative growth of corticospinal tract axons via the ventral column after spinal cord injury in mice. J. Neurosci., 28, 6836-6847.
Chotiner, J.K., Nielson, J., Farris, S., Lewandowski, G., Huang, F., Banos, K., deLeon, R., and Steward, O. (2010). Assessment of the role of MAP kinase in mediating activity-dependent transcriptional activation of the immediate early gene Arc/Arg3.1 in the dentate gyrus in vivo. Learning and Memory, 17, 117-129.
Liu, K., Lu, Y., Lee, J.K., Samara, R., Willenberg, R., Sears-Kraxberger, I., Tedeshi, A., Park, K.K., Jin, D., Cai, B., Zu, B., Connolly, L., Steward, O., Zheng, B., and He, Z. (2010) PTEN deletion promotes sprouting and regeneration of corticospinal axons after spinal cord injury. Nature Neurosci. 13,1075-1083 (Cover Photograph).
Nielson, J.L., Sears-Kraxberger, I., Wong, J., Strong, M., Willenberg, R., and Steward, O. (2010) Unexpected survival of neurons of origin of the pyramidal tract after spinal cord injury. J. Neurosci. 30, 11516-11528.
Huntley, G.W., Elset, A.M., Patil, S.B., Bozdai, O., Benson, D.L., and Steward, O. (2010) Synaptic loss and retention of different classic cadherins with LTP-associated synaptic structural remodeling in vivo. Hippocampus. 2010 Sep 16. doi: 10.1002/hipo.20859. [Epub ahead of print].
Neurobiology and Behavior
Interdepartmental Neuroscience Program
Cellular and Molecular Biosciences
|Research Center||Reeve-Irvine Research Center|
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