http://uu.diva-portal.org/smash/record.jsf?pid=diva2:585197
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.
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