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Functional and histological outcome after focal traumatic brain injury is not improved in conditional EphA4 knockout mice

Hånell, Anders; Clausen, Fredrik; Djupsjö, Anders; Vallstedt, Anna; Patra, Kalicharan; Israelsson, Charlotte; Larhammar, Martin; Björk, Maria; Paixão, Sónia and Kullander, Klas, et al. (2012) In Journal of Neurotrauma 29(17). p.71-2660
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.... (More)

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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Animals, Blotting, Western, Body Weight, Brain Injuries, Female, Glial Fibrillary Acidic Protein, Immunohistochemistry, Lameness, Animal, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Postural Balance, Real-Time Polymerase Chain Reaction, Receptor, EphA4, Sex Characteristics, Journal Article, Research Support, Non-U.S. Gov't
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Journal of Neurotrauma
volume
29
issue
17
pages
71 - 2660
publisher
Mary Ann Liebert, Inc.
external identifiers
  • scopus:84870537753
ISSN
1557-9042
DOI
10.1089/neu.2012.2376
language
English
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55f8f3c9-496f-4079-aac8-2e3637ea41c6
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2016-12-12 15:49:59
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2017-05-28 04:55:38
@article{55f8f3c9-496f-4079-aac8-2e3637ea41c6,
  abstract     = {<p>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&lt;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&lt;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&lt;0.05) and hippocampal sprouting (Timm stain, p&lt;0.05) and induced a marked loss of hemispheric tissue (p&lt;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.</p>},
  author       = {Hånell, Anders and Clausen, Fredrik and Djupsjö, Anders and Vallstedt, Anna and Patra, Kalicharan and Israelsson, Charlotte and Larhammar, Martin and Björk, Maria and Paixão, Sónia and Kullander, Klas and Marklund, Niklas},
  issn         = {1557-9042},
  keyword      = {Animals,Blotting, Western,Body Weight,Brain Injuries,Female,Glial Fibrillary Acidic Protein,Immunohistochemistry,Lameness, Animal,Male,Maze Learning,Mice,Mice, Inbred C57BL,Mice, Knockout,Motor Activity,Postural Balance,Real-Time Polymerase Chain Reaction,Receptor, EphA4,Sex Characteristics,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {11},
  number       = {17},
  pages        = {71--2660},
  publisher    = {Mary Ann Liebert, Inc.},
  series       = {Journal of Neurotrauma},
  title        = {Functional and histological outcome after focal traumatic brain injury is not improved in conditional EphA4 knockout mice},
  url          = {http://dx.doi.org/10.1089/neu.2012.2376},
  volume       = {29},
  year         = {2012},
}