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Development of in vitro epileptic seizure models to study the expression and potential roles of microRNAs in epilepsy

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Title: Development of in vitro epileptic seizure models to study the expression and potential roles of microRNAs in epilepsy
Author: Parmentier, Thomas
Department: Department of Biomedical Sciences
Program: Biomedical Sciences
Advisor: LaMarre, Jonathan
Abstract: Epilepsy is one of the most common brain disorders, occurring naturally in several mammalian species. Importantly, 20-30% of human and canine epileptic patients are not well controlled with current treatment for epilepsy, highlighting the need for disease-modifying therapies. One of the mechanisms underlying epilepsy progression and its associated cognitive dysfunction is the formation of new, abnormal neurons after seizures, a phenomenon known as seizure-induced neurogenesis. How neural stem cells respond to seizures to form these abnormal neurons is not well understood, partly due to the difficulty of accessing the brains of humans and dogs ante-mortem to study the underlying mechanisms. Among several potential mechanisms, microRNA-mediated control of gene expression after seizures is an attractive candidate as microRNAs (miRNAs) are important regulators of neurogenesis and are known to be dysregulated in epilepsy. In this dissertation, we first investigate if human cerebral organoids generated from induced pluripotent stem cells can generate seizure-like activity in vitro and if this activity influences neurogenesis. While human cerebral organoids did not fully recapitulate complex seizure-like events, the increase in neuronal activity was associated with increased neurogenesis and decreased gliogenesis. To study similar mechanisms in dogs, we attempted to generate canine cerebral organoids from canine embryonic stem cells (cESCs) using a similar protocol. Interestingly, the canine cerebral organoids generated did not recapitulate the layered organization of human cerebral organoids and more closely resembled neurospheres. However, canine neurons and glial cells could be obtained from cESCs in 2D (monolayer) culture. Finally, we explored the dysregulation of miRNA expression in human cerebral organoids and in cESC-derived neural cells exposed to pro-epileptic conditions, as well as in the hippocampus of epileptic dogs. We identify miR-135a, a miRNA previously associated with neurogenesis, to be dysregulated in all three models. We then start to investigate potential functions of miR-135a to mediate activity-induced neurogenesis. Together, these epilepsy models pave the way to study the role of miRNA in epilepsy-induced neurogenesis which could lead to the identification of new therapeutic targets.
URI: https://hdl.handle.net/10214/26371
Date: 2021-08-27
Rights: Attribution-NonCommercial 4.0 International
Embargoed Until: 2022-08-26


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Attribution-NonCommercial 4.0 International Except where otherwise noted, this item's license is described as Attribution-NonCommercial 4.0 International