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Scn8a is a neuronal
Na+ channel that contributes to the ‘classical’ transient Na+
current during an action potential, and in some neurons also
mediates distinct subthreshold currents that affect firing
patterns and excitability. Different mutations in Scn8a cause a
spectrum of neurologic dysfunction, including tremor, ataxia,
dystonia, paresis, and paralysis. However, because the gene is
expressed in so many places in the central, peripheral, and
enteric nervous systems, the resulting phenotypes are difficult
to study due to their complexity. We have used the approach of
generating conditional or targeted mutations in restricted cell
types in mice to better understand the role of this gene in
specific neural pathways.
Recent work in my lab (and in
conjunction with collaborators) includes three major projects.
One line of investigation has been to elucidate the spatial
distribution of Scn8a and other related sodium channel genes in
the enteric nervous system with the objective of better
understanding the determinants of neuronal excitability in the
gut. A second project has been directed at understanding a
possible novel and unexpected role of this gene in the heart.
Most recently, we have developed a novel mouse model of dystonia
using the targeted gene inactivation approach.
Dystonia is a movement
disorder typified by sustained abnormal postures and twisting
movements. The anatomic origin(s) and pathophysiology of
dystonia are poorly understood. Secondary dystonias have been
associated with lesions of the basal ganglia, but clinical or
experimental evidence for a similar origin of primary dystonias
is lacking. Scn8a mutant mice constitute the first association
of an ion channelopathy with dystonia. These mice should help to
clarify the role of Scn8a in specific regions of the brain and
spinal cord, and their respective contributions to dystonia.
Biographical Information
Leslie Sprunger received a
B.S. in Biological Science from the University of Alaska, Fairbanks (1983), a
D.V.M. from Washington State University (1987), and entered private practice
as a small animal veterinarian. Dr. Sprunger returned to academia to earn a
Ph.D. in Physiology (1995) from the University of Minnesota Department of
Veterinary Pathobiology, where she was the recipient of a Graduate School
Fellowship, the Louise T. Dosdall Fellowship for Women in Science, the Charles
and Dorothy Andrew Bird Award for Research, and a Howard Hughes Medical
Institute predoctoral fellowship. An NIH Clinical Investigator Development
Award funded Dr. Sprunger’s post-doctoral training in the University of
Minnesota Medical School Department of Physiology, and the Department of Human
Genetics at the University of Michigan Medical School. Dr. Sprunger was
appointed research faculty at University of Michigan in 1999, and joined the
Department of VCAPP as Assistant Professor in July 2000.
Selected Publications
Raman, I.M., L.K.
Sprunger, M.H. Meisler, and B.P. Bean. (1997) Altered subthreshold sodium
currents and disrupted firing patterns in Purkinje neurons of Scn8a mutant
mice. Neuron, 19:881-891.
Garcia, K., L.K.
Sprunger, M.H. Meisler, and K. Beam. (1998) Postnatal development of
sodium current density in normal and med motoneurons. J. Neurosci.,
18:5234-5239.
Sprunger, L.K.,
A. Escayg, S. Tallaksen-Greene, R.L. Albin, and M.H. Meisler. (1999)
Generalized dystonia associated with mutation of the neuronal sodium channel
Scn8a: role of the modifier locus Scnm1 on mouse chromosome 3. Hum. Mol.
Genet. 8:471-479.
Buchner, D.A., M. Trudeau, A.L. George, L.K. Sprunger,
and M.H. Meisler. (2003) High resolution mapping of the sodium
channel modifier Scnm1 on mouse chromosome 3 and identification
of a 1.3 kb recombination hotspot. Genomics 82(4): 452-459.
Meisler, M.H., N.W. Plummer, D.L. Burgess, D.A. Buchner, and
L.K. Sprunger. (2004) Allelic mutations of the sodium
channel SCN8A reveal multiple cellular and physiological
functions. Genetica (Netherlands) 122: 37-45.
Sprunger, L.K., and T.L. Smith. (2005) Reorganizing
small animal gross anatomy: improving the faculty and student
experience and incorporating non-technical competency
development. J. Vet. Med. Educ. 32: 255-263.
Bartoo, A.C., L.K. Sprunger, and D.A. Schneider. (2005)
Expression and distribution of TTX-sensitive sodium channel
alpha subunits in the enteric nervous system. J. Comp. Neurol.
406: 117-131.
Bartoo, A.C., L.K. Sprunger, and D.A. Schneider. (2006)
Expression of the sodium channel Nav1.2 in chemically identified
myenteric neurons in the guinea pig. Cell Tiss. Res. 324(1):
25-32.
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