| Associate Professor Department of Neurosciences |
 |
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)
.
Current Research Interests:
Our lab is interested in basic mechanisms that contribute to cell death in the central nervous system. 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 two aspects of this process.
| The
major focus of our laboratory involves studies of excitotoxic mechanisms
in restricted regions of nerve dendrites. We have found that glutamate receptor
agonists initiate sustained Ca2+ elevations at these sites, and that these
“secondary Ca2+ responses” then spread very slowly throughout
neurons and lead to cell death. 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 will provide
important new approaches to limiting cell death. We have exploited differences
in excitotoxic vulnerability between inbred murine strains (C57Bl/6 and
C57Bl/10) to demonstrate the involvement of these responses in excitotoxic
cell death in intact slice preparations. These studies are performed in
acute brain slice preparations, utilizing whole-cell electrophysiological
recordings, combined with CCD-based fluorescence imaging of Ca2+ indicators.
As well as implicating dendritic secondary responses as key determinants
of excitotoxic vulnerability, this work provides novel preparations that
permit new investigations of: 1) mechanisms underlying secondary response initiation, 2) mechanisms by which secondary responses spread through dendritic processes 3) how secondary responses trigger cellular damage. |
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A second major interest of our laboratory has become imaging studies of mitochondrial function in acute brain slices. Excitotoxic Ca2+ signaling can lead to profound disruptions in mitochondrial function, and there is strong evidence that mitochondrial dysfunction can play a critical role in neuronal damage. We have studied the relationship between neuronal Ca2+ transients and dynamics of mitochondrial NADH, using intrinsic fluorescence imaging. We have found a surprising dissociation between neuronal Ca2+ influx and NADH transients, and found this approach to be a sensitive monitor of the postsynaptic neuronal activity, even following quite mild physiological stimuli. Ongoing studies are investigating the impact of excitotoxic stimuli on mitochondrial function, using NADH fluorescence imaging, and imaging of mitochondrial potential. These studies involve single- and multiphoton imaging measurements from subregions of hippocampal slices, as well as from single CA1 pyramidal neurons in studies of whole-cell clamped neurons. |
Key References:
Shuttleworth CW, Connor JA. Strain-dependent differences in calcium signaling
predict excitotoxicity in murine hippocampal neurons. J
Neurosci. 2001 Jun 15;21(12):4225-36.
Connor, J.A. and C.W. Shuttleworth. Intracellular Ca2+ signals underlying rapid
and delayed neuronal death in mature CNS neurons. In: R.C.S. Lin, Ed., New
Concepts in Cerebral Ischemia, CRC Press (2001)113-134.
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.
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.
Lab Personnel:
Zuzana Sumbalova Ph.D. (Postdoctoral Fellow)
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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