Electronic Thesis and Dissertation Repository

Thesis Format



Master of Science




Brown, Arthur


After an episode of repetitive mild traumatic brain injury (rmTBI), many cellular and molecular cascades are initiated that result in the disruption of the structural and chemical integrity of the components in the brain, leading to the development of various cognitive deficits. The goal of this thesis was to evaluate a mouse model of concussion in order to study the relationship between rmTBI, GSK3β and tau phosphorylation, and behavioural outcomes in a transgenic mouse line expressing solely human tau. We found that there was increased phosphorylation of the two main regulatory sites on GSK3β, Tyr216 and Ser9, in the C57BL/6 mice. When investigating the pathology and behaviour in the MAPT KI mice, there was positive silver staining, pathological tau staining (AT8), and increased Iba1 staining compared to shams, with animals displaying cognitive deficits upon behavioural testing. Overall, this study supports the use of MAPT KI transgenic mice in rmTBI studies.

Summary for Lay Audience

Traumatic brain injuries (TBIs) are injuries that affect the structural integrity of the brain which, in turn, has a negative impact on brain functions and influences the behaviour of those affected. The least severe form of TBIs, known as mild TBIs (mTBIs) includes concussions and sub-concussive closed head injuries. When the exposure to mTBIs becomes repetitive, in other words repetitive mild traumatic brain injuries (rmTBI), there is an increased risk for the development of a neurodegenerative disease known as Chronic Traumatic Encephalopathy (CTE). The main characteristic of this disease is the presence of abnormal tau protein aggregates in the brain. One protein that has been implicated in the process of formation of these abnormal protein aggregates is called glycogen synthase kinase 3-beta (GSK3β).

There is always the struggle of taking results from scientific studies involving animal models and then applying them to human beings. However, technological advancements have allowed the development of genetic tools that have been applied to rodents in order to create ideal models with greater clinical relevance to human disease. In this thesis I investigate a novel mouse model in which the entire mouse tau gene has been replaced with the human tau gene. I use this mouse model to characterize the structural damage, at the cellular and molecular levels, that occur post-rmTBI, as well as the behavioural outcomes, in order to validate the use of this model in future research.

This study demonstrates that the novel mouse model is capable of developing the cellular and molecular injuries typical of rmTBIs. The mice also demonstrate behavioural deficits that correlate with rmTBI injury, similar to that seen in humans. Overall, this study supports the use of these mice for future rmTBI studies, as these mice are more clinically relevant and therefore more desirable models. This study will hopefully serve as a stepping stone for future studies of rmTBI with a focus on further characterizing the pathology and developing and applying potential therapeutics.