Elsevier

Experimental Neurology

Volume 149, Issue 1, January 1998, Pages 221-229
Experimental Neurology

Regular Article
Mechanisms of Motor Recovery after Subtotal Spinal Cord Injury: Insights from the Study of Mice Carrying a Mutation (WldS) That Delays Cellular Responses to Injury

https://doi.org/10.1006/exnr.1997.6717Get rights and content

Abstract

Partial lesions of the mammalian spinal cord result in an immediate motor impairment that recovers gradually over time; however, the cellular mechanisms responsible for the transient nature of this paralysis have not been defined. A unique opportunity to identify those injury-induced cellular responses that mediate the recovery of function has arisen from the discovery of a unique mutant strain of mice in which the onset of Wallerian degeneration is dramatically delayed. In this strain of mice (designatedWldSfor Wallerian degeneration, slow), many of the cellular responses to spinal cord injury are also delayed. We have used this experimental animal model to evaluate possible causal relationships between these delayed cellular responses and the onset of functional recovery. For this purpose, we have compared the time course of locomotor recovery in C57BL/6 (control) mice and inWldS(mutant) mice by hemisecting the spinal cord at T8 and evaluating locomotor function at daily postoperative intervals. The time course of locomotor recovery (as determined by the Tarlov open-field walking procedure) was substantially delayed in mice carrying theWldSmutation: C57BL/6 control mice began to stand and walk within 6 days (mean Tarlov score of 4), whereas mutant mice did not exhibit comparable locomotor function until 16 days postoperatively. Interpretation and conclusion: (a) The rapid return of locomotor function in the C57BL/6 mice suggests that the recovery resulted from processes of functional plasticity rather than from regeneration or collateral sprouting of nerve fibers. (b) The marked delay in the return of locomotor function inWldSmice indicates that the processes of neuroplasticity are induced by degenerative changes in the damaged neurons. (c) These strains of mice can be effectively used in future studies to elucidate the specific biochemical and physiological alterations responsible for inducing functional plasticity and restoring locomotor function after spinal cord injury.

References (61)

  • L. Guth

    Functional plasticity in the respiratory pathway of the mammalian spinal cord

    Exp. Neurol.

    (1976)
  • L. Guth et al.

    Spinal cord injury in the rat: Treatment with bacterial lipopolysaccharide and indomethacin enhances cellular repair and locomotor function

    Exp. Neurol.

    (1994)
  • R.M. Harris et al.

    Spared descending pathways mediate locomotor recovery after subtotal spinal cord injury

    Neurosci. Lett.

    (1994)
  • M. Kato et al.

    Recovery of postural control following chronic bilateral hemisections at different spinal cord levels in adult cats

    Exp. Neurol.

    (1985)
  • J. Krikorian et al.

    Origin of the connective tissue scar in the transected rat spinal cord

    Exp. Neurol.

    (1981)
  • J.P. Kuhtz-Buschbeck et al.

    Recovery of locomotion after spinal cord hemisection: An X-ray study of the cat hindlimb

    Exp. Neurol.

    (1996)
  • E. Kunkel-Bagden et al.

    Recovery of function after spinal cord hemisection in newborn and adult rats: Differential effects on reflex and locomotor function

    Exp. Neurol.

    (1992)
  • S.K. Ludwin et al.

    Delayed wallerian degeneration in the central nervous system of Ola mice: An ultrastructural study

    J. Neurol. Sci.

    (1992)
  • P.G. Popovich et al.

    A quantitative spatial analysis of the blood-spinal cord barrier. I. Permeability changes after experimental contusion injury

    Exp. Neurol.

    (1996)
  • Y. Saruhashi et al.

    The recovery of 5-HT immunoreactivity in lumbosacral spinal cord and locomotor function after thoracic hemisection

    Exp. Neurol.

    (1996)
  • H.S. Sharma et al.

    Prostaglandins modulate alterations of microvascular permeability, blood flow, edema and serotonin levels following spinal cord injury: an experimental study in the rat

    Neuroscience

    (1993)
  • O. Steward

    Signals that induce sprouting in the central nervous system: Sprouting is delayed in strain of mouse exhibiting delayed axonal degeneration

    Exp. Neurol.

    (1992)
  • C.E. Thomson et al.

    Retarded Wallerian degeneration following peripheral nerve transection in C57BL/6/Ola mice is associated with delayed down-regulation of the P0 gene

    Brain Res.

    (1991)
  • S.G. Waxman et al.

    Enhancement of action potential conduction following demyelination: Experimental approaches to restoration of function in multiple sclerosis and spinal cord injury

    Prog. Brain Res.

    (1994)
  • J.H. Williams

    Retrograde messengers and long-term potentiation: A progress report

    J. Lipid Mediat. Cell Signal.

    (1996)
  • J.R. Wrathall et al.

    Spinal cord contusion in the rat: production of graded, reproducible, injury groups

    Exp. Neurol.

    (1985)
  • Z.C. Zhang et al.

    Experimental analysis of progressive necrosis after spinal cord trauma in the rat: The etiologic role of inflammatory responses

    Exp. Neurol.

    (1997)
  • R.P. Abelson et al.

    Efficient conversion of nonparametric information into a metric system

    The Quantitative Analysis of Social Problems

    (1970)
  • D.K. Anderson et al.

    Effects of treatment with U-74006F on neurological outcome following experimental spinal cord injury

    J. Neurosurg.

    (1988)
  • M.B. Bracken et al.

    Effects of timing of methylprednisolone or naloxone administration on recovery of segmental and long-tract neurological function in NASCIS 2

    J. Neurosurg.

    (1993)
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