title: Functional and histological outcome after focal traumatic brain injury is not improved in conditional EphA4 knockout mice.
abstract: We investigated the role of the axon guidance molecule EphA4 following traumatic brain injury (TBI) in mice. Neutralization of EphA4 improved motor function and axonal regeneration following experimental spinal cord injury (SCI). We hypothesized that genetic absence of EphA4 could improve functional and histological outcome following TBI. Using qRT-PCR in wild-type (WT) mice, we evaluated the EphA4 mRNA levels following controlled cortical impact (CCI) TBI or sham injury and found it to be downregulated in the hippocampus (p<0.05) but not the cortex ipsilateral to the injury at 24 h post-injury. Next, we evaluated the behavioral and histological outcome following CCI using WT mice and Emx1-Cre-driven conditional knockout (cKO) mice. In cKO mice, EphA4 was completely absent in the hippocampus and markedly reduced in the cortical regions from embryonic day 16, which was confirmed using Western blot analysis. EphA4 cKO mice had similar learning and memory abilities at 3 weeks post-TBI compared to WT controls, although brain-injured animals performed worse than sham-injured controls (p<0.05). EphA4 cKO mice performed similarly to WT mice in the rotarod and cylinder tests of motor function up to 29 days post-injury. TBI increased cortical and hippocampal astrocytosis (GFAP immunohistochemistry, p<0.05) and hippocampal sprouting (Timm stain, p<0.05) and induced a marked loss of hemispheric tissue (p<0.05). EphA4 cKO did not alter the histological outcome. Although our results may argue against a beneficial role for EphA4 in the recovery process following TBI, further studies including post-injury pharmacological neutralization of EphA4 are needed to define the role for EphA4 following TBI.
authors.affiliation: Section for Neurosurgery, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hånell
authors.forename: Fredrik
authors.initials: F
authors.lastname: Clausen
authors.forename: Anders
authors.initials: A
authors.lastname: Djupsjö
authors.forename: Anna
authors.initials: A
authors.lastname: Vallstedt
authors.forename: Kalicharan
authors.initials: K
authors.lastname: Patra
authors.forename: Charlotte
authors.initials: C
authors.lastname: Israelsson
authors.forename: Martin
authors.initials: M
authors.lastname: Larhammar
authors.forename: Maria
authors.initials: M
authors.lastname: Björk
authors.forename: Sónia
authors.initials: S
authors.lastname: Paixão
authors.forename: Klas
authors.initials: K
authors.lastname: Kullander
authors.forename: Niklas
authors.initials: N
authors.lastname: Marklund
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D001930:Brain Injuries / Q000473:pathology* / Q000523:psychology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D007794:Lameness, Animal / Q000209:etiology / Q000523:psychology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D004856:Postural Balance / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D036122:Receptor, EphA4 / Q000235:genetics* / Q000502:physiology; D012727:Sex Characteristics
chemical_list: D005904:Glial Fibrillary Acidic Protein; D036122:Receptor, EphA4