Genetic Factors in Excitotoxicity and Stroke

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Copyright: Bi, Mian
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Abstract
Excitotoxicity refers to the damaging and toxic effects inflicted upon neuronal tissue resulting from excessive or prolonged activation of excitatory receptors. It has been implicated in many neurological conditions ranging from epilepsy to stroke and chronic neurodegenerative conditions like Alzheimer’s disease. In the first part of this thesis, we utilised a tau deficient mouse to demonstrate that the lack of tau protects against excitotoxic brain injury after experimental stroke. Furthermore, we showed that this protection is due to site-specific inhibition of Ras/ERK-mediated toxicity by the post-synaptic accumulation of a Ras-inhibiting protein known as SynGAP1. We were able to reverse this protection via viral-mediated knockdown of SynGAP1 in tau deficient mice. Conversely, in vitro over-expression of SynGAP1 prevented excitotoxic ERK signalling in wild-type neurons. This makes tau relevant in acute excitotoxic conditions like stroke making tau relevant beyond neurodegenerative diseases such as Alzheimer’s disease. Next, we utilised a new murine genetic reference population known as the Collaborative Cross to screen for genes implicated in excitotoxicity via a chemical induced epileptic seizure model. After successful identification of two potential candidates, Lamp5 & 4933407L21Rik, we utilised CRISPR-mediated genetic editing to delete our candidate genes and confirmed the observed phenotype in both strains. To our knowledge, this is the first time susceptibility genes for a complex trait have been identified and confirmed in the Collaborative Cross mice using both forward and reverse genetic approaches. In summary, we demonstrated the role tau plays in mediating excitotoxicity and stroke; as well as identified and confirmed two new seizure susceptibility genes that have not been previously described.
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Author(s)
Bi, Mian
Supervisor(s)
Ittner, Lars
Gunning, Peter
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Publication Year
2018
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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