CDKL5 disorder is a devastating neurodevelopmental disorder characterized by early-onset seizures, intellectual disability, and autistic-like features. It is caused by mutations in a single X-linked gene, cyclin-dependent kinase-like 5 (CDKL5) and affects predominantly heterozygous girls but also some hemizygous boys. Studies have shown the CDKL5 protein to be localized, at least in part, to the excitatory synapse, and that it interacts with proteins of the postsynaptic density. Interestingly, CDKL5 protein expression rises significantly in the postnatal period, correlating with the time window of synaptogenesis. However, the in vivo consequences of CDKL5 loss on excitatory synapse development and function remain unclear. In this project, I propose to investigate the cell-autonomous functions of CDKL5 in vivo in excitatory neurons, through the generation of a cell type-specific knockout mouse line (Nex-cKO). Given my preliminary data on altered dendritic spine density and excitatory synaptic function in adult Nex-cKO mice, I propose additional experiments to characterize the consequences of CDKL5 loss on synapse development and animal behavior.

Public Health Relevance

CDKL5 disorder is a rare but devastating childhood neurologic disorder. Children with mutations in the CDKL5 gene suffer from seizures and severe intellectual disability, yet no specific treatments are currently available. This project aims to probe the mechanism for CDKL5 disorder and expand the preclinical knowledge base for the eventual development of rational, targeted therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS100433-02
Application #
9451936
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Mamounas, Laura
Project Start
2017-02-01
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
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
Tang, Sheng; Wang, I-Ting Judy; Yue, Cuiyong et al. (2017) Loss of CDKL5 in Glutamatergic Neurons Disrupts Hippocampal Microcircuitry and Leads to Memory Impairment in Mice. J Neurosci 37:7420-7437