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Steven A. Siegelbaum, Ph.D.
Professor of Neuroscience and Pharmacology
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Research
Summary
Molecular studies of ion channel structure and function; synaptic transmission and plasticity in the mammalian brain.
We are interested in the molecular and cellular mechanisms underlying electrical signaling and synaptic transmission in the nervous system. One set of questions is focused on a class of ion channels that is important for generating spontaneous rhythmic activity in nerve and muscle cells. These channels are activated by hyperpolarization and generate slow, pacemaker depolarizations by conducting positively charged sodium ions into a cell. The pacemaker channels are modulated by the direct binding of cyclic nucleotides, which speeds up the rate of channel activation and thus speeds the rate of cell firing. We have recently shown that the pacemaker channels are members of a novel gene family, related to the family of voltage-gated potassium channels activated by depolarization. We are interested in the underlying structural mechanisms by which cyclic nucleotide binding alters channel gating. We are also interested in the unique gating mechanisms of these channels: Why are they activated by hyperpolarization whereas related K+ channels are activated by depolarization? Finally, using mouse genetics, we investigate the role of these channels in brain function and behavior.
In a separate set of experiments, we analyze the cellular and molecular mechanisms underlying different forms of long-term, activity-dependent synaptic plasticity in the mammalian hippocampus, key processes thought to underlie learning and memory. Using both electrophysiological methods and two-photon optical imaging, we investigate both functional changes in synaptic transmission as well as structural changes likely to contribute to long-term plasticity. We specifically monitor presynaptic function by imaging a fluorescent dye that is selectively loaded into and released from synaptic vesicles as a function of neuronal activity. By combining these measurements with mouse genetics, in which specific genes are deleted or overexpressed in specific brain regions, we are exploring the molecular mechanisms that underlie the induction and expression of synaptic plasticity. Our ultimate goal is to correlate defects in specific forms of plasticity with defects in specific aspects of learning and memory.
http://neuroscience.columbia.edu/department/index.php?ID=27&bio=189
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Selected Publications:
1. Zakharenko, S., Zablow, L. Siegelbaum, S.A. (2002) Altered presynaptic vesicle release and cycling during mGluR dependent LTD. Neuron
35:1099-1110.
2. Wang, J., Chen, S., Nolan, M.F. and Siegelbaum, S.A. (2002) Activity-dependent regulation of HCN pacemaker channels by cAMP: Signaling through dynamic allosteric coupling Neuron
36:451-461.
3. Ulens, C. and Siegelbaum, S.A. (2003) Stoichiometry of cAMP modulation mediated by a C-terminal gating ring in HCN pacemaker channels. Neuron
40:959-970.
4. Nolan, M.F., Malleret, G., Dudman, J.T., Buhl, D.L., Santoro, B., Gibbs, E., Vronskaya, S., Buzsáki, G., Siegelbaum, S.A.,Nolan, M.F., Malleret, G., Dudman, J.T., Buhl, D.L., Santoro, B., Gibbs, E., Vronskaya, S., Buzsáki, G., Siegelbaum, S.A., Cell
119:719-732.
5. Lang C, Barco A, Zablow L, Kandel ER, Siegelbaum SA,Zakharenko SS. (2004). Transient expansion of synaptically connected dendritic spines upon induction of hippocampal long-term potentiation. Proc Natl Acad Sci U S A
101:16665-16670.
6. Zhou L, Olivier NB, Yao H, Young EC, Siegelbaum SA. (2004) A Conserved Tripeptide in CNG and HCN Channels Regulates Ligand Gating by Controlling C-Terminal Oligomerization Neuron
44:823-834
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Honors and Awards
Alfred P. Sloan Research Fellowship
Irma T. Hirschl Career Scientist Award
Herbert J. Kayden Award of the New York Academy of Sciences in Biomedical Science
Committees
Editorial Board, Journal of Neurophysiology
Associate Editor, Neuron
Associate Editor, Journal of Neuroscience (1997-2002)
Editorial Board, Journal of General Physiology
Council & Executive Committee, Biophysical Society (1999-2002)
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