Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice

Neuroscience. 2009 Oct 6;163(2):540-51. doi: 10.1016/j.neuroscience.2009.06.042. Epub 2009 Jun 23.

Abstract

Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS axons may recover poorly following TBI due to expression of myelin-derived inhibitors to axonal outgrowth such as Nogo-A. To study the role of Nogo-A/B in the pathophysiological response of the elderly to TBI, 1-year-old mice deficient in Nogo-A/B (Nogo-A/B homozygous(-/-) mice), Nogo-A/B heterozygous(-/+) mice, and age-matched wild-type (WT) littermate controls were subjected to a controlled cortical impact (CCI) TBI. Sham-injured WT mice (7 months old) and 12 month old naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) served as controls. Neurological motor function was evaluated up to 3 weeks, and cognitive function, hemispheric tissue loss, myelin staining and hippocampal beta-amyloid (A beta) immunohistochemistry were evaluated at 4 weeks post-injury. In WT littermates, TBI significantly impaired learning ability at 4 weeks and neurological motor function up to 2 weeks post-injury and caused a significant loss of hemispheric tissue. Following TBI, Nogo-A/B(-/-) mice showed significantly less recovery from neurological motor and cognitive deficits compared to brain-injured WT mice. Naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) mice quickly learned the MWM task in contrast to brain-injured Nogo-A/B(-/-) mice who failed to learn the MWM task at 4 weeks post-injury. Hemispheric tissue loss and cortical lesion volume were similar among the brain-injured genotypes. Neither TBI nor the absence of NogoA/B caused an increased A beta expression. Myelin staining showed a reduced area and density in the corpus callosum in brain-injured Nogo-A/B(-/-) animals compared to their littermate controls. These novel and unexpected behavioral results demonstrate that the absence of Nogo-A/B may negatively influence outcome, possibly related to hypomyelination, following TBI in mice and suggest a complex role for this myelin-associated axonal growth inhibitor following TBI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain Injuries / pathology
  • Brain Injuries / physiopathology*
  • Cognition Disorders / pathology
  • Cognition Disorders / physiopathology
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin Proteins / deficiency*
  • Myelin Proteins / genetics
  • Myelin Proteins / metabolism
  • Myelin Sheath / metabolism
  • Myelin Sheath / pathology
  • Neuropsychological Tests
  • Nogo Proteins
  • Organ Size
  • Random Allocation
  • Recovery of Function / physiology*
  • Time Factors
  • Treatment Outcome

Substances

  • Amyloid beta-Peptides
  • Myelin Proteins
  • Nogo Proteins
  • Rtn4 protein, mouse