Differential Expression Patterns of TDP-43 in Single Moderate versus Repetitive Mild Traumatic Brain Injury in Mice.

Tamara Janković,Nika Gržeta,Kristina Pilipović,Gordana Župan,Jelena Rajič Bumber,Jasna Kriz,Petra Dolenec

doi:10.3390/ijms222212211

Abstract

Traumatic brain injury (TBI) is a disabling disorder and a major cause of death and disability in the world. Both single and repetitive traumas affect the brain acutely but can also lead to chronic neurodegenerative changes. Clinical studies have shown some dissimilarities in transactive response DNA binding protein 43 (TDP-43) expression patterns following single versus repetitive TBI. We explored the acute cortical post-traumatic changes of TDP-43 using the lateral fluid percussion injury (LFPI) model of single moderate TBI in adult male mice and investigated the association of TDP-43 with post-traumatic neuroinflammation and synaptic plasticity. In the ipsilateral cortices of animals following LFPI, we found changes in the cytoplasmic and nuclear levels of TDP-43 and the decreased expression of postsynaptic protein 95 within the first 3 d post-injury. Subacute pathological changes of TDP-43 in the hippocampi of animals following LFPI and in mice exposed to repetitive mild TBI (rmTBI) were studied. Changes in the hippocampal TDP-43 expression patterns at 14 d following different brain trauma procedures showed pathological alterations only after single moderate, but not following rmTBI. Hippocampal LFPI-induced TDP-43 pathology was not accompanied by the microglial reaction, contrary to the findings after rmTBI, suggesting that different types of brain trauma may cause diverse pathophysiological changes in the brain, specifically related to the TDP-43 protein as well as to the microglial reaction. Taken together, our findings may contribute to a better understanding of the pathophysiological events following brain trauma.

Highlights

Traumatic brain injury (TBI) is one of the most common causes of disability and death in younger individuals [1,2,3]
In the ipsilateral cortices of injured animals, increased cytoplasmic transactive response DNA binding protein 43 (TDP-43) immunostaining was evident at both day 1 and day 3 after the brain trauma compared to the control mouse, in which this protein was mostly situated in the cell nuclei (Figure 1A)
We wanted to determine whether these TDP-43 expression changes are cell type specific, i.e., if the increased cytoplasmic presence of this protein could be detected in the ipsilateral cortical neurons, microglia, or astrocytes after lateral fluid percussion injury (LFPI)

Summary

Introduction

Traumatic brain injury (TBI) is one of the most common causes of disability and death in younger individuals [1,2,3]. It was once predicted to surpass many other conditions as a major cause of death and disability in an overall population by the year 2020 [4]. The majority of patients hospitalized due to brain trauma are diagnosed with mild TBI, while moderate and severe TBIs are rarer, with an overall ratio of 22:1.5:1 [2]. Mild injuries occur multiple times, in athletes involved in contact sports [6,7], the military personnel [8,9], and the victims of domestic violence [10]

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Conclusion