Genetic deletion and pharmacological inhibition of Nogo-66 receptor impairs cognitive outcome after traumatic brain injury in mice

Research output: Contribution to journalArticle

Abstract

Functional recovery is markedly restricted following traumatic brain injury (TBI), partly due to myelin-associated inhibitors including Nogo-A, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp), that all bind to the Nogo-66 receptor-1 (NgR1). In previous studies, pharmacological neutralization of both Nogo-A and MAG improved outcome following TBI in the rat, and neutralization of NgR1 improved outcome following spinal cord injury and stroke in rodent models. However, the behavioral and histological effects of NgR1 inhibition have not previously been evaluated in TBI. We hypothesized that NgR1 negatively influences behavioral recovery following TBI, and evaluated NgR1(-/-) mice (NgR1(-/-) study) and, in a separate study, soluble NgR1 infused intracerebroventricularly immediately post-injury to neutralize NgR1 (sNgR1 study) following TBI in mice using a controlled cortical impact (CCI) injury model. In both studies, motor function, TBI-induced loss of tissue, and hippocampal beta-amyloid immunohistochemistry were not altered up to 5 weeks post-injury. Surprisingly, cognitive function (as evaluated with the Morris water maze at 4 weeks post-injury) was significantly impaired both in NgR1(-/-) mice and in mice treated with soluble NgR1. In the sNgR1 study, we evaluated hippocampal mossy fiber sprouting using the Timm stain and found it to be increased at 5 weeks following TBI. Neutralization of NgR1 significantly increased mossy fiber sprouting in sham-injured animals, but not in brain-injured animals. Our data suggest a complex role for myelin-associated inhibitors in the behavioral recovery process following TBI, and urge caution when inhibiting NgR1 in the early post-injury period.

Details

Authors
  • Anders Hånell
  • Fredrik Clausen
  • Maria Björk
  • Kristine Jansson
  • Ola Philipson
  • Lars N G Nilsson
  • Lars Hillered
  • Paul H Weinreb
  • Daniel Lee
  • Tracy K McIntosh
  • David A Gimbel
  • Stephen M Strittmatter
  • Niklas Marklund
Organisations
External organisations
  • Uppsala University
Research areas and keywords

Keywords

  • Animals, Brain Injuries, Cognition Disorders, Disease Models, Animal, Female, GPI-Linked Proteins, Gene Deletion, Injections, Intraventricular, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myelin Proteins, Receptors, Cell Surface, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
Original languageEnglish
Pages (from-to)1297-309
Number of pages13
JournalJournal of Neurotrauma
Volume27
Issue number7
Publication statusPublished - 2010 Jul
Publication categoryResearch
Peer-reviewedYes