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From Healthy to Epileptic Brain: Molecular Contributors to Epileptogenesis

McGann, Amanda
http://orcid.org/0000-0002-4167-6483
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712911405077967

Abstract Details

2024, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
Epilepsy affects over 50 million patients worldwide, and one-third of those patients are resistant to current therapeutic options. The development of acquired epilepsy typically begins with a brain insult such as status epilepticus (SE), traumatic brain injury, genetic mutation, or infection. Following such insults, patients enter what is known as the “latent period” of the disease. During the latent period, the brain is changing but patients do not exhibit spontaneous recurrent seizures (SRSs). The latent period ends when a patient first experiences an SRS, at which point the disease has progressed to epilepsy. Epileptogenesis is the process by which a healthy brain becomes prone to SRSs, and it occurs during initial insult as well as throughout the latent period and chronic disease. While the majority of available treatment options aim to reduce SRSs in patients with chronic epilepsy, research has increasingly sought to define and inhibit epileptogenic changes. Successful anti-epileptogenic intervention has the potential to prevent or delay the onset of chronic epilepsy following brain insult and/or prevent continued brain alterations in patients who have already developed chronic epilepsy. The work in this thesis aimed to clarify the molecular mechanisms underlying epileptogenesis. Chapters 2 and 3 discuss the role of microRNAs (miRNAs) in epileptogenesis, and Chapter 4 discusses the role of Ras-MAPK signaling in epileptogenesis. MiRNAs are short, non-coding RNA sequences that regulate post-transcriptional gene expression via translational suppression or degradation of target messenger RNAs (mRNAs). Although many miRNAs have been implicated in epilepsy development, this thesis primarily discusses the role of miR-324-5p. Previous work in our lab showed an anti-convulsant and anti-epileptic effect of miR-324-5p inhibition when administered before brain insult or in chronic epilepsy. Using the intrahippocampal kainic acid model in mice, we tested the hypothesis that miR-324-5p inhibition during epileptogenesis would delay or prevent SRSs (Chapter 2) and enable identification of mRNAs targeted by miR-324-5p during epileptogenesis (Chapter 3). Overall, our results indicated that miR-324-5p inhibition during epileptogenesis is not sufficient to delay or prevent epilepsy development, but it does alter EEG power spectra and the genetic landscape of hippocampal cells. The Ras-MAPK pathway regulates a number of critical biological functions. Disorders related to germline mutations in components of the pathway are categorized as “Rasopathies,” and several of these disorders present with epilepsy. In Chapter 4 of this thesis, we use the intraperitoneal kainic acid model to test the hypothesis that a mouse model of a novel ERK2 (MAPK1) gain-of-function Rasopathy would display increased seizure susceptibility. Our results indicate sex-specific effects of kainic acid administration, with female heterozygous gain-of-function mice exhibiting higher seizure susceptibility than wildtype female mice and no differences in susceptibility based on genotype in male mice. The work in this thesis adds to the field’s understanding of the molecular mechanisms underlying epileptogenesis, discusses the interplay between molecular mediators, and offers considerations for future investigations. There is an urgent need for continued investigation into all aspects of epilepsy development to identify novel solutions for epilepsy patients.
Mark Baccei, Ph.D. (Committee Chair)
Christina Gross, Ph.D. (Committee Member)
Katrina Peariso, M.D. Ph (Committee Member)
Anil Jegga, DVM MRe (Committee Member)
Steve Danzer, Ph.D. (Committee Member)
217 p.
Neurology
epilepsy; epileptogenesis; microRNA; Ras-MAPK; ERK2; EEG

Recommended Citations

Citations

  • McGann, A. (2024). From Healthy to Epileptic Brain: Molecular Contributors to Epileptogenesis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712911405077967

    APA Style (7th edition)

  • McGann, Amanda. From Healthy to Epileptic Brain: Molecular Contributors to Epileptogenesis. 2024. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712911405077967.

    MLA Style (8th edition)

  • McGann, Amanda. "From Healthy to Epileptic Brain: Molecular Contributors to Epileptogenesis." Doctoral dissertation, University of Cincinnati, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712911405077967

    Chicago Manual of Style (17th edition)

ucin1712911405077967
© 2024, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.