title: Genetic deletion and pharmacological inhibition of Nogo-66 receptor impairs cognitive outcome after traumatic brain injury in mice.
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.
authors.affiliation: Department of Neurosurgery, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hånell
authors.forename: Fredrik
authors.initials: F
authors.lastname: Clausen
authors.forename: Maria
authors.initials: M
authors.lastname: Björk
authors.forename: Kristine
authors.initials: K
authors.lastname: Jansson
authors.forename: Ola
authors.initials: O
authors.lastname: Philipson
authors.forename: Lars N G
authors.initials: LN
authors.lastname: Nilsson
authors.forename: Lars
authors.initials: L
authors.lastname: Hillered
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.forename: Daniel
authors.initials: D
authors.lastname: Lee
authors.forename: Tracy K
authors.initials: TK
authors.lastname: McIntosh
authors.forename: David A
authors.initials: DA
authors.lastname: Gimbel
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
authors.forename: Niklas
authors.initials: N
authors.lastname: Marklund
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D003072:Cognition Disorders / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D017353:Gene Deletion; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D000070816:Nogo Receptor 1; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology
chemical_list: D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; D011956:Receptors, Cell Surface; C419790:Rtn4r protein, mouse