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Title: Characterising gene regulation during epileptogenesis in different models of epilepsy
Author: Chang, Bao-Luen
ISNI:       0000 0004 7229 2356
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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As epilepsy develops an enormous range of changes occurs in neurons. This process, epileptogenesis, involves complex spatiotemporal alterations of neuronal homeostasis and neural networks. The molecular mechanism of epileptogenesis remains obscure and gene regulation during the epileptogenic process dynamically controls various signalling and functional pathways which play an important role in defining the mechanisms of epilepsy. This thesis explores gene regulation in different in vitro models of seizure like activity, and further focuses on the temporal profiles of molecular changes during an in vivo model of epilepsy. We seek to identify important regulators of epileptogenesis which may be the targets for further study of the mechanism of epilepsy in human. The High-K+, Low-Mg2+, Kainic acid, and Pentylenetetrazole models were used to elicit seizure like activity in cortical neuronal cultures. The tetanus toxin (TeNT) model of focal neocortical epilepsy in rats was utilised to characterise gene regulation in different time points: acute, subacute and chronic stages (48-72 hours, 2 weeks, and 30 days after first spontaneous seizure, respectively). A set of candidate genes relevant to epilepsy was selected to analyse changes in mRNA expression during these in vitro and in vivo models. The mRNA expression of the different candidate genes reveals diverse regulatory behaviours in different models, as well as at different time points during the process of epileptogenesis. The cell culture model treated with Low-Mg2+ for 72 hours displayed the most similar mRNA expression profile to the in vivo model of TeNT neocortical epilepsy during subacute to chronic stages. Furthermore, in the in vivo model, GFAP, mTOR, REST, and SNAP-25 are all temporarily apparently up-regulated during epileptogenesis, while CCL2 is strongly up-regulated later when epilepsy is established. Transient down-regulation of BDNF in the acute stage, and the distinctly lower expression of GABRA5 in late stage suggest that this GABAergic signalling pathway may be down-regulated in the late phase of epileptogenesis. Our work highlights how different candidate genes are differentially regulated during epileptogenesis, and how the regulation of individual genes changes as epileptogenesis progresses.
Supervisor: Schorge, Stephanie ; Walker, Matthew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available