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Phosphatase and tensin homolog (PTEN) induced abnormalities in a mouse model of epilepsy

Arafa, Salwa
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1521192488305689

Abstract Details

2018, PhD, University of Cincinnati, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics.
Epilepsy is a disease characterized by recurrent and unprovoked seizures. Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy and is often refractory to treatment. Hypothetically, it originates in the temporal lobe of the brain, when the dentate gyrus (DG) of the hippocampus becomes compromised, which, otherwise, physiologically functions as a “filtering gate” to hyperexcitatory signals. Animal models were developed to outline mechanisms by which epilepsy occurs. In 2012, Pun and colleagues have proven that deleting a gene, phosphatase and tensin homologue (PTEN) can cause epilepsy in mice. PTEN is an inhibitor in the mammalian target of rapamycin (mTOR) pathway. Deleting PTEN causes mTOR hyperactivation which leads to cellular changes that are considered hallmarks of the disease, for example: somatic and dendritic hypertrophy and appearance of aberrant basal dendrites. Despite the plethora of knowledge about the disease, it is still unknown how the morphological abnormalities develop with age, and whether or not, they are caused, at least in part, by seizures and what are the gender specific difference in the excitability and/or morphology in the model. Our guiding hypothesis is that PTEN deletion leads to cell intrinsic changes which worsen overtime. Further, we hypothesize that disease severity may cause those changes to worsen in male and female mice. In chapter II, we modified the PTEN KO model of epilepsy to produce a “mild” phenotype in order to examine the growth trajectories of the PTEN knockout (KO) cells. Three different cohorts were used: 1) brainbow-expressing mice with low KO numbers that don’t develop seizures and have an age range of 7-18 weeks, 2) biocytin-filled cells from animals with low KO numbers that don’t develop spontaneous seizures and have a wide age range (15-36 weeks), and 3) biocytin-filled cells from animals with high KO numbers and a severe seizure phenotype. Findings from chapter II indicate that the onset of abnormalities in DGCs is 4 weeks after PTEN deletion and worsens with time regardless of the presence or absence of seizures; which favors the alternative hypothesis that disease severity doesn’t impact morphological abnormalities. In Chapter III, we investigated whether there are sex specific differences in the model. We conducted electrophysiology experiments in acute hippocampal slices from PTEN KO male and female mice followed by morphological analyses. Findings indicate that there are no distinctive morphological differences in the PTEN KO cell abnormalities related to sex. Findings in chapters II and III are novel and may influence the design and the optimum intervention timing with mTOR inhibitors in diseases linked to mTOR hyperactivation such as tuberous sclerosis (TSC) and genetic epilepsy. In chapter IV, we explored alternative approaches to delete PTEN. We injected a GFP-cre retrovirus into 6-8 weeks old PTEN flox/flox mice to delete PTEN and label cells in postnatally born DGCs. As a future aim, we will use a pseudotyped rabies virus to label the synaptic partners of PTEN KOs. Results will reveal the cell populations involved in driving the hippocampal circuitry towards hyperexcitation which is hypothesized to occur in epilepsy.
Steve Danzer, Ph.D. (Committee Chair)
Steve Crone, Ph.D. (Committee Member)
Gary Gudelsky, Ph.D. (Committee Member)
Katherine Holland-Bouley, M.D. Ph.D. (Committee Member)
Jianxiong Jiang, Ph.D. (Committee Member)
181 p.
Neurology
PTEN; mTOR; Epilepsy; Brainbow; Biocytin

Recommended Citations

Citations

  • Arafa, S. (2018). Phosphatase and tensin homolog (PTEN) induced abnormalities in a mouse model of epilepsy [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1521192488305689

    APA Style (7th edition)

  • Arafa, Salwa. Phosphatase and tensin homolog (PTEN) induced abnormalities in a mouse model of epilepsy. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1521192488305689.

    MLA Style (8th edition)

  • Arafa, Salwa. "Phosphatase and tensin homolog (PTEN) induced abnormalities in a mouse model of epilepsy." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1521192488305689

    Chicago Manual of Style (17th edition)

ucin1521192488305689
266
© 2018, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.
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