Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Zhaolan Zhou

Abstract

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.

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