[Abstract Title]. - Society for Neuroscience

Poster
251. Demyelinating Disorders: Animal Models and Human Studies I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 251.10/W3
Topic: C.08.b. Animal models
Support: NS 37475
NMSS RG3618
Title: Correlation between transverse bands and lifespan in dysmyelinated mice
Authors: *J. ROSENBLUTH 1,4 , A. MIERZWA 2 , J. AREVALO 5 , M. CHAO 3,6 ;
1 Dept Physiol., 2 Physiol. and Neurosci., 3 Mol. Neurobio. Program, New York Univ. Sch. Med.,
New York, NY; 4 Rusk Inst., New York, NY; 5 INCYL-Facultad de Medicina, Salamanca, Spain;
6 Skirball Inst. of Biomolecular Med., New York Univ. Sch. of Med., New York, NY
Abstract: The spontaneous mouse mutant „shaking‟ (Mierzwa et al., SFN Abstract 277.17, 2005
and Mierzwa et al., SFN Abstract 975.20, 2004) has minimal PNS pathology but severe CNS
dysmyelination. Homozygous mice display a mild kinetic tremor and seizures in 10-20% of the
animals. Their hindlimbs do not clasp when the mice are lifted by the tail, and they can hang by
front or hindlimbs, indicating no signs of muscle weakness. They differ strikingly from other
„myelin mutants‟ with comparable CNS dysmyelination in that their lifespan is near-normal,
with animals living past two years of age. Other mutants, such as Caspr -/- and CGT -/-, with
grossly similar levels of dysmyelination have more severe behavioral phenotypes and lifespans
under six months. In this poster, we present data showing that „shaking‟ mice differ markedly
from other dysmyelinating mutants with respect to the transverse bands (TB) and other features
of their paranodes. Cervical dorsal spinal cord of control, CST -/- and shaking animals aged
1.5mo to 12mo was sectioned and examined at 25K magnification by EM. The percentage of
paranodal loops directly contacting the axolemma was similar in control and shaking animals but
significantly reduced in the CST-/-. Correspondingly, the percentage of paranodes with TBs was
comparable in control and „shaking‟ mice but significantly reduced in the CST-/- animals, and
those paranodes lacking transverse bands were more likely to have everted loops. Previous
studies have shown that CGT-/- and Caspr-/- mice, which are more severely affected than
„shaking‟, lack transverse bands entirely. CST-/- mice show decreasing numbers of TBs with age
corresponding to the worsening phenotype. In mutants lacking TBs, axolemmal domains are
abnormal in that the nodal Na+
channel domain lengthens and may become non-circumferential, and the fast voltage-gated K+
channels, normally confined to the juxtaparanode, move into the paranode. Our findings suggest
that the presence of transverse bands is important in maintaining paranodal structure, axoglial
domains, and subsequently function. Those mutants that lack or have grossly reduced numbers of
TBs have more severe deficits and shortened lifespans.