Graduation Date

Spring 5-9-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Genetics, Cell Biology & Anatomy

First Advisor

Jyothi Arikkath

Abstract

CDKL5 Deficiency Disorder (CDD) is an X-linked neurodevelopmental disorder associated with epilepsy, developmental retardation, autism, and related phenotypes. Currently, there is no cure available for the disorder. Thus, the identification of cellular and molecular aberrations in this disorder and the generation and validation of mouse models that recapitulate core aspects of the disorder are a pressing need in the field. Our studies are aimed at filling this gap.

Mutations in the CDKL5 gene, encoding CDKL5, have been identified in this disorder. CDKL5 is a protein with homology to the serine-threonine kinases and incompletely characterized function. Mutations in CDKL5 are predominately localized in the kinase domain of the protein, suggesting that a compromise of the kinase activity is a key component of the pathology of the disorder.

Our data indicate that genetic loss of CDKL5 in glutamatergic or GABAergic neurons of the cortex and striatum, respectively, in murine models differentially alters expression of some components of the mechanistic target of rapamycin (mTOR) signaling pathway and synaptic markers in a neuron-type specific manner. Thus, loss of CDKL5 leads to molecular aberrations that are specific to neuronal subtypes in the cortex and striatum. Further, our studies indicate that a mouse model bearing a human CDD mutation that does not result in a protein-null phenotype recapitulates core behavioral aspects of the disorder, including motor and learning impairments and may be a good model for the disorder.

Taken together, these studies identify some molecular aberrations that underlie CDD and validate a mouse model for CDD. Future studies can be directed at correcting these aberrations and taking advantage of the CDD mouse models to identify and correct other molecular deficits that can be targeted pharmacologically, thus paving the way for therapy in this devastating disorder.

Available for download on Sunday, May 01, 2022

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