Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


27847.pdf (3.87 MB)

ETD Abstract Container

Abstract Header

Targeting Newly Generated Dentate Granule Cells as a Treatment for Epilepsy

Hosford, Bethany E
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504792093299792

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
Granule cells are one of the few neuronal populations that continue to be born throughout life and into old age. The protracted development of this cell population appears to make it uniquely vulnerable to anatomical and physiological abnormalities following epileptogenic insults. Under normal conditions, this cell population typically is located densely in the granule cell body layer of the hippocampus, projects its dendritic trees outwardly through the molecular layer to the edges of the hippocampal fissure, and sends its mossy fiber axons inwardly to the hilus and CA3. However, following an epileptogenic insult, the defined arrangement of dentate granule cells becomes unstructured. Interestingly, it is the newly generated granule cells that are more prone to improper migration and cellular development. Furthermore, newly generated dentate granule cells exhibit striking physiological changes including depolarized membrane potentials, prolonged action potentials, spontaneous bursting, and increased firing. At the same time, the dentate gyrus becomes less capable at limiting the amount of synaptic flow through the hippocampus. These data underlie the hypothesis that newly generated dentate granule cells are pro-epileptogenic. To test this hypothesis I have completed studies which aim at decreasing granule cell anatomic and physiologic abnormalities. In the first study (chapter 2), I used the mTOR inhibitor rapamycin to try to prevent the improper development of dentate granule cells following pilocarpine-induced status epilepticus. The mTOR pathway is involved in cell growth and division, making it a promising candidate target to inhibit aberrant cell development. Rapamycin treatment prevented aberrant axonal sprouting, but had no effect on other hippocampal pathologies. Interestingly, treatment also inhibited epilepsy induced weight gain. In the second study (chapter 3), I used a novel transgenic approach to target newly generated dentate granule cells prior to pilocarpine-induced status epilepticus. These cells were then ablated shortly following the epileptogenic injury. Results of this study demonstrated that removing the cells prophylactically could reduce the number of ectopically located granule cells and also reduce seizure frequency several weeks later. As a follow up to this study, the project described in the final study (chapter 4) used the same transgenic approach to target newly generated granule cells; however, cell ablation occurred months after the injury. In this study, treatment prevented further increases in seizure frequency, and also resulted in a robust reduction of ectopically located granule cells. The studies conducted as a part of this dissertation research demonstrate that newly generated dentate granule cells are contributing to the formation of seizures in the pilocarpine model of temporal lobe epilepsy. The data supports the hypothesis that these effects are driven in part by ectopically located granule cells generated after the epileptogenic insult. Finally, this data provides the first line of evidence that targeting newly born dentate granule cells could lead to new therapeutic approaches for patients with epilepsy, especially since treatment was effective at inhibiting seizure progression when applied months after spontaneous seizure onset.
Christina Gross, Ph.D. (Committee Chair)
Mark Baccei, Ph.D. (Committee Member)
Steve Crone, Ph.D. (Committee Member)
Steve Danzer, Ph.D. (Committee Member)
Katherine Holland-Bouley, M.D. Ph.D. (Committee Member)
182 p.
Neurology
epilepsy; neurogenesis; dentate granule cells; hippocampus; dentate gyrus; cell ablation

Recommended Citations

Citations

  • Hosford, B. E. (2017). Targeting Newly Generated Dentate Granule Cells as a Treatment for Epilepsy [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504792093299792

    APA Style (7th edition)

  • Hosford, Bethany. Targeting Newly Generated Dentate Granule Cells as a Treatment for Epilepsy. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504792093299792.

    MLA Style (8th edition)

  • Hosford, Bethany. "Targeting Newly Generated Dentate Granule Cells as a Treatment for Epilepsy." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504792093299792

    Chicago Manual of Style (17th edition)

ucin1504792093299792
393
© 2017, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.