Temporal and molecular insights into the pathophysiology of CDKL5 deficiency disorder / Barbara Terzic.

Format:

Book

Thesis/Dissertation

Author/Creator:

Terzic, Barbara, author.

Contributor:

Zhou, Zhaolan, degree supervisor.

University of Pennsylvania. Department of Neuroscience, degree granting institution.

Language:

English

Subjects (All):

Neurosciences.

Pathology.

Neuroscience--Penn dissertations.

Penn dissertations--Neuroscience.

Local Subjects:

Neurosciences.

Pathology.

Neuroscience--Penn dissertations.

Penn dissertations--Neuroscience.

Genre:

Academic theses.

Physical Description:

1 online resource (209 pages)

Contained In:

Dissertations Abstracts International 82-07B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2020.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

CDKL5 deficiency disorder (CDD) is a severe, neurodevelopmental disorder associated with lesions in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene. Despite the simple genetic etiology of CDD its pathophysiology remains poorly understood, and the treatability of specific CDD symptoms is untested. Using genetically modified mouse models of CDD, we demonstrate that aberrant glutamatergic signaling through NMDA receptors underlies the disrupted circuit hyperexcitability connected to several CDD-related deficits in mice. We also temporally manipulated endogenous Cdkl5 expression, and find that post-developmental loss of CDKL5 disrupts numerous behavioral domains, hippocampal circuit communication, and dendritic spine morphology, demonstrating an indispensable role for CDKL5 in the adult brain. Accordingly, adult restoration of Cdkl5 in knockout mice significantly ameliorates CDD-related behavioral impairments and aberrant NMDA receptor signaling. These results demonstrate that adult neural function requires CDKL5, and suggest chronic treatment may be required in CDD. Furthermore, our results uncover a broad therapeutic time window for numerous CDD-related deficits, and substantiate aberrant NMDA receptor signaling as underlying numerous CDD pathologies. These discoveries expand upon our current understanding of CDKL5 in regulating neurological function, and comprise a critical foundation for future studies aiming to develop therapeutics for CDD patients, especially beyond the early developmental time window.

Notes:

Source: Dissertations Abstracts International, Volume: 82-07, Section: B.

Advisors: Zhou, Zhaolan; Committee members: Marc Fuccillo; Erika Holzbaur; Wenqin Luo; Eric Marsh.

Department: Neuroscience.

Ph.D. University of Pennsylvania 2020.

Local Notes:

School code: 0175

ISBN:

9798557058919

Access Restriction:

Restricted for use by site license.

This item must not be sold to any third party vendors.