Related Experiment Video
Updated: Jan 20, 2026
Modeling Behavioral Disorders and Stress in Rodents
Published on: April 30, 2023
Pharmacotherapy with sertraline rescues brain development and behavior in a mouse model of CDKL5 deficiency disorder
Claudia Fuchs1, Laura Gennaccaro1, Elisa Ren1
1Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
Abstract:
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a severe neurodevelopmental disorder, CDKL5 deficiency disorder (CDD). CDKL5 is fundamental for correct brain development and function, but the molecular mechanisms underlying aberrant neurologic dysfunction in CDD are incompletely understood. Here we show a dysregulation of hippocampal and cortical serotonergic (5-HT) receptor expression in heterozygous Cdkl5 knockout (KO) female mice, suggesting that impaired 5-HT neurotransmission contributes to CDD. We demonstrate that targeting impaired 5-HT signaling via the selective serotonin reuptake inhibitor (SSRI) sertraline rescues CDD-related neurodevelopmental and behavioral defects in heterozygous Cdkl5 KO female mice. In particular, chronic treatment with sertraline normalized locomotion, stereotypic and autistic-like features, and spatial memory in Cdkl5 KO mice. These positive behavioral effects were accompanied by restored neuronal survival, dendritic development and synaptic connectivity. At a molecular level, sertraline increased brain-derived neurotrophic factor (BDNF) expression and restored abnormal phosphorylation levels of tyrosine kinase B (TrkB) and its downstream target the extracellular signal-regulated kinase (ERK1/2). Since sertraline is an FDA-approved drug with an extensive safety and tolerability data package, even for children, our findings suggest that sertraline may improve neurodevelopment in children with CDD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
Insights
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder involves impaired serotonin signaling. Treatment with sertraline, a selective serotonin reuptake inhibitor (SSRI), improved neurodevelopmental and behavioral deficits in a mouse model of CDD.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Mutations in the X-linked CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition.
- The precise molecular mechanisms underlying CDD's neurological dysfunction remain unclear.
- Serotonergic (5-HT) system dysregulation is implicated in CDD pathogenesis.
Purpose of the Study:
- To investigate the role of 5-HT neurotransmission in CDD.
- To evaluate the therapeutic potential of targeting 5-HT signaling in CDD.
- To explore the molecular underpinnings of CDD-related neurodevelopmental deficits.
Main Methods:
- Utilized heterozygous Cdkl5 knockout (KO) female mice as a model for CDD.
- Administered the selective serotonin reuptake inhibitor (SSRI) sertraline.
- Assessed behavioral phenotypes, neuronal survival, dendritic development, synaptic connectivity, and molecular markers including BDNF, TrkB, and ERK1/2 phosphorylation.
Main Results:
- Cdkl5 KO mice exhibited dysregulated hippocampal and cortical 5-HT receptor expression.
- Sertraline treatment rescued neurodevelopmental and behavioral defects in Cdkl5 KO mice, including normalized locomotion, stereotypic and autistic-like behaviors, and spatial memory.
- Sertraline administration restored neuronal survival, dendritic complexity, synaptic connectivity, and modulated key molecular pathways (BDNF, TrkB, ERK1/2).
Conclusions:
- Impaired 5-HT neurotransmission is a significant contributor to CDD.
- Targeting 5-HT signaling with SSRIs like sertraline shows promise for treating CDD.
- Sertraline's established safety profile suggests its potential as a therapeutic intervention for children with CDD.
Related Concept Videos
10:17An Introduction to Modeling Behavioral Disorders and Stress
07:31Murine Drinking Models in the Development of Pharmacotherapies for Alcoholism: Drinking in the Dark and Two-bottle Choice
05:21Establishment of A Mouse Model of Aqueous Deficiency Dry Eye
11:05Behavioral Characterization of an Angelman Syndrome Mouse Model
08:30Paradigms for Behavioral Assessment in Drosophila Model of Autism Spectrum Disorder
09:44Evaluating Therapeutic Interventions in the SHIP-deficient Mouse Model of Crohn Disease-like Ileitis and Fibrosis