MIT Libraries logoDSpace@MIT

MIT
View Item 
  • DSpace@MIT Home
  • MIT Libraries
  • MIT Theses
  • Graduate Theses
  • View Item
  • DSpace@MIT Home
  • MIT Libraries
  • MIT Theses
  • Graduate Theses
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Generation of focal Depdc5 knockout mouse model and implications for focal epilepsy

Author(s)
Groff, Karenna J.
Thumbnail
DownloadThesis PDF (13.45Mb)
Advisor
Dedon, Peter
Yuskaitis, Christopher
Terms of use
In Copyright - Educational Use Permitted Copyright retained by author(s) https://rightsstatements.org/page/InC-EDU/1.0/
Metadata
Show full item record
Abstract
Epilepsy is a neurological disorder that impacts more than 65 million individuals globally, and one in every 200 children. DEPDC5 is the most commonly identified gene associated with familial focal epilepsy and malformations of cortical development. It is also associated with an increased risk of Sudden-Unexplained Death in Epilepsy (SUDEP). It remains unknown whether seizures due to DEPDC5 loss are a result of in utero cortical developmental defects or later neuronal dysfunction of mTORC1 signaling. To test this, we developed a postnatal adeno-associated virus (AAV) mediated focal cortical Depdc5 knockout mouse model. Viral vectors containing either 2/8AAV-Cre or control 2/8AAV-GFP were injected into the unilateral motor cortex of postnatal day zero or day one Depdc5 floxed (Depdc5c/c or Depdc5c/-) mouse pups. We confirmed a significant reduction in DEPDC5 levels and increased mTOR activity in the AAV-Cre injected hemisphere compared to the contralateral hemisphere or control AAV-GFP injected mice. Cortical lamination was not disrupted by AAV-Cre or AAV-GFP injection. Focal Depdc5 knockout mice have lowered seizure thresholds and increased mortality from seizures. Acute fasting is protective against seizures in a DEPDC5-dependent manner, which is facilitated by the control hemisphere of focal Depdc5 knockout mice. Focal Depdc5 knockout mice have increased cortical thickness, increased cortical neuron size and dysplastic neurons throughout the cortex, similar to the abnormal neurons seen in human focal cortical dysplasia specimens. Glial abnormalities in the Depdc5 knockout region are identified, such as hypomyelination, reactive astrogliosis, and microglial activation. Our focal Depdc5 knockout mouse model recapitulates clinical, pathological, and biochemical features of human DEPDC5-related epilepsy and brain malformations. Our study reveals that postnatal DEPDC5 loss without disruption of cortical migration is sufficient to cause epilepsy and SUDEP. Restoration of DEPDC5 function via gene therapy represents a viable treatment approach.
Date issued
2023-06
URI
https://hdl.handle.net/1721.1/151978
Department
Massachusetts Institute of Technology. Department of Biological Engineering
Publisher
Massachusetts Institute of Technology

Collections
  • Graduate Theses

Browse

All of DSpaceCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

My Account

Login

Statistics

OA StatisticsStatistics by CountryStatistics by Department
MIT Libraries
PrivacyPermissionsAccessibilityContact us
MIT
Content created by the MIT Libraries, CC BY-NC unless otherwise noted. Notify us about copyright concerns.