# Pathogenic Studies of CDKL5 Disorder

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $538,031

## Abstract

Title
Pathogenic Studies of CDKL5 Disorder
Abstract
Mutations in the X-linked gene encoding cyclin-dependent kinase-like 5 cause CDKL5 disorder, an infantile epileptic
encephalopathy sharing features with intellectual disability and autism. To understand the biological function of CDKL5
in vivo and the pathogenic mechanisms underlying CDKL5 disorder, we previously developed and characterized a
knockout mouse model incorporating a CDKL5 patient-associated genetic defect. We found that mice with CDKL5
dysfunction develop behavioral phenotypes mimicking key symptoms of CDKL5 disorder. These mice also show deficits
in neural circuit communication and alterations in multiple signal transduction pathways. Given that CDKL5 expression is
highly enriched in the forebrain, we also employed a conditional knockout approach and ablated CDKL5 expression in
different neuronal populations of the forebrain. We found that mice lacking CDKL5 from different neuronal cells show
distinct behavioral phenotypes, mimicking intellectual disability-like and autism-like features of CDKL5 disorder. These
findings raise a hypothesis that CDKL5 regulates cell type-specific signal transduction pathways and different neural
circuit mechanisms underlying intellectual disability and autistic features of CDKL5 disorder. We therefore propose to
develop an innovative mouse line to characterize cell type-specific functions of CDKL5, and take a combined
biochemical, genetic, behavioral, and neurophysiological approach to investigate the molecular and cellular basis of
CDKL5 disorder using knockout and conditional knockout mice in both male and females. Together, we expect to
uncover new aspects of CDKL5 function, develop a framework for testing therapeutics, and ultimately reveal new
opportunities for therapeutic development to alleviate symptoms associated with CDKL5 disorder, as well as other related
disorders such as syndromic intellectual disability and autism.

## Key facts

- **NIH application ID:** 9893035
- **Project number:** 5R01NS102731-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Zhaolan Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $538,031
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893035

## Citation

> US National Institutes of Health, RePORTER application 9893035, Pathogenic Studies of CDKL5 Disorder (5R01NS102731-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9893035. Licensed CC0.

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