Investigating excitatory neuronal function across development in CDKL5 disorder

University Of Pennsylvania, Philadelphia PA

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Abstract

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.