Mutations in the X-linked gene encoding cyclin-dependent kinase-like 5 (CDKL5) cause the childhood epileptic encephalopathy known as CDKL5 disorder. The disease is characterized by a heterogeneous array of clinical symptoms including early-onset seizures, marked hypotonia, autistic-like features, and severe neurodevelopmental impairment. To confirm the genetic causality of CDKL5 disorder, we generated the first Cdkl5 knockout (KO) mouse and found that mice lacking CDKL5 mirror several hallmark symptoms of the human disease, including autistic-like behaviors, impaired motor control, disrupted auditory-evoked event- related potentials, and poor learning and memory. Interestingly, Cdkl5 KO mice also exhibit perturbed dendritic spine density, morphology, and LTP. These early findings suggest an important role for CDKL5 in neuronal synapse function. However, CDKL5?s specific role in this context, particularly post-development, remains unknown. Given these synaptic phenotypes caused by CDKL5 loss, and my recent preliminary data using a novel adult KO model of CDKL5, I hypothesize that CDKL5 expression is required in adulthood to maintain proper synaptic homeostasis, circuit communication, and behavioral output. Thus, the goal of this proposal is to elucidate the adulthood requirement of CDKL5 in synaptic function by 1) determining the sufficiency of CDKL5 in restoring loss-of-function circuit and behavioral deficits at adulthood and 2) determining the extent to which CDKL5 modulates synaptic density and morphology in vivo. My ultimate goal is to determine a novel role for CDKL5 in the maintenance of adult neural function. These studies will provide essential preclinical information regarding disease reversibility, and pave the way for the future development of more targeted therapeutics for CDKL5 disorder patients.

Public Health Relevance

CDKL5 disorder is a rare, but devastating, neurodevelopmental affliction linked to mutations in the CDKL5 gene. Patients suffer from early-onset seizures, autistic-like features, and severe neurodevelopmental impairment, yet no specific treatments are currently available. This proposal aims to understand the requirement of CDKL5 at neuronal synapses, and to test the reversibility of CDKL5 disorder phenotypes with the hopes of eventually furthering the development of more targeted therapeutics for patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS101762-01A1
Application #
9469699
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mamounas, Laura
Project Start
2017-09-19
Project End
2019-09-18
Budget Start
2017-09-19
Budget End
2018-09-18
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104