| Associate Professor Department of Neurosciences |
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Education and Honors:
B.Sc. Adelaide University (1984-6);
B.Sc. (Hons). Flinders University of South Australia (1987);
Ph.D. University of Melbourne (1988-91).
Postdoctoral Training University of Nevada School of Medicine (1992-1995)
Research Assistant Professor, University of Nevada (1995-8).
Chancellor's Letter of Commendation (1987);
Smith Klein & French Neuroscience prize (1988);
Australian Postgraduate Research Award (1988-1991);
Fellow Award XV International Symposium on Gastrointestinal motility (1995);
Khatali Teaching Award (2004, 2006, 2008).
Current Research Interests:
Our lab is interested in basic mechanisms that contribute to cell death in the central nervous system.
One major interest involves mechanisms of neuronal Ca2+ overload. A common triggering event in neurodegeneration is widely held to be the excessive release of the excitatory transmitter glutamate, and subsequent massive Ca2+ influx. This process has been termed “excitotoxicity”, and we are currently working on the roles of dendrite metabolism in initiation of excitotoxic injury Our hypothesis is that fine dendrites, being richly endowed with Ca2+-permeable glutamate receptors and channels, act as initiation sites of excitotoxic Ca2+ signals, and that procedures to prevent the initiation and/or spread of secondary Ca2+ responses may provide important new approaches to limiting cell death [1-3]. |
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A second area of interest involves mechanisms of spreading depression. Spreading depression (SD) involves waves of profound neuronal and glial depolarization that spread throughout brain tissue. Under many conditions, tissue recovers full function after SD has occurred, but SD-like events are also associated with spread of injury following ischemia or trauma. In recent work, we have investigated the relationship between Ca2+ and Zn2+ entry that occurs during SD, and found that Zn2+ accumulation can be critically involved in some forms of SD that are relevant to ischemic injury [4]. |
Localized disruption of normal metabolism has emerged as an important upstream initiator of dendritic Ca2+ overload and also determines the degree of injury produced by SD. We have undertaken imaging studies of mitochondrial function, using probes of mitochondrial potential and also intrinsic fluorescence imaging to study mitochondrial NADH [5,6]. Current work is investigating possible contributions of Zn2+ to initial mitochondrial dysfunction.
Main Experimental Approaches:
Brain slice electrophysiology combined with fluorescence imaging:
Whole cell, intracellular, extracellular recordings
Fluorescent indicators for cations, mitochondrial potential, intrinsic fluorescence
(Conventional epifluorescence and 2 photon)
Immunohistochemistry, confocal microscopy.
Key References:
1. Shuttleworth, C.W.R. and Connor, J.A., Strain-dependent differences in calcium signaling predict excitotoxicity in murine hippocampal neurons J. Neurosci. 21 (2001) 4225-36.
2. VanderJagt, T.A., Connor, J.A. & Shuttleworth, C.W. Localized loss of Ca2+ homeostasis in neuronal dendrites as a downstream consequence of metabolic compromise during extended NMDA exposures. J. Neurosci. 28 (2008) 5029-5039.
3. Hoskison, M.M. and Shuttleworth, C.W. Microtubule disruption, not calpain-dependent loss of MAP2, contributes to enduring NMDA-induced dendritic dysfunction in acute hippocampal slices. Experimental Neurology 202 (2006) 302-12.
4. Shuttleworth CW, Brennan AM, Connor JA. NAD(P)H fluorescence imaging of postsynaptic neuronal activation in murine hippocampal slices. J Neurosci. 2003 Apr 15;23(8):3196-208.
5. Brennan, A.M., Connor, J.A., Shuttleworth, C.W. NAD(P)H fluorescence transients after synaptic activity in brain slices: predominant role of mitochondrial function. J. Cereb Blood Flow Metab. 2006 Mar 14 Epub.
6. Dietz, R.M., Weiss, J.H. & Shuttleworth, C.W. Zn2+ influx is critical for some forms of spreading depression in brain slices. Journal of Neuroscience 28 (2008) 8014-8024
Lab Personnel:
Thom Vander Jagt (Graduate Student)
Robert Dietz (Graduate Student)
Jessica Seidel (Graduate Student)
Contact:
Bill Shuttleworth, Ph.D.
bshuttleworth@salud.unm.edu
Office: (505) 272 4290
Lab: (505) 272 0616
Fax: (505) 272 8082
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