Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder.

Claudia Fuchs,Roberto Rimondini,Elisa Ren,Giovanna Zoccoli,Stefania Trazzi,Viviana Lo Martire,Giorgio Medici,Elisabetta Ciani,Laura Gennaccaro,Simone Bettini,Stefano Bastianini

doi:10.1155/2018/9726950

Claudia Fuchs, Roberto Rimondini + Show 9 more

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https://doi.org/10.1155/2018/9726950

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Abstract

CDKL5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 (cyclin-dependent kinase-like five) gene. CDKL5 disorder primarily affects girls and is characterized by early-onset epileptic seizures, gross motor impairment, intellectual disability, and autistic features. Although all CDKL5 female patients are heterozygous, the most valid disease-related model, the heterozygous female Cdkl5 knockout (Cdkl5 +/−) mouse, has been little characterized. The lack of detailed behavioral profiling of this model remains a crucial gap that must be addressed in order to advance preclinical studies. Here, we provide a behavioral and molecular characterization of heterozygous Cdkl5 +/− mice. We found that Cdkl5 +/− mice reliably recapitulate several aspects of CDKL5 disorder, including autistic-like behaviors, defects in motor coordination and memory performance, and breathing abnormalities. These defects are associated with neuroanatomical alterations, such as reduced dendritic arborization and spine density of hippocampal neurons. Interestingly, Cdkl5 +/− mice show age-related alterations in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling, two crucial signaling pathways involved in many neurodevelopmental processes. In conclusion, our study provides a comprehensive overview of neurobehavioral phenotypes of heterozygous female Cdkl5 +/− mice and demonstrates that the heterozygous female might be a valuable animal model in preclinical studies on CDKL5 disorder.

Highlights

Cyclin-dependent kinase-like 5 (CDKL5) disorder (OMIM no. 300203) is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 gene
Due to the different CDKL5 mutations and the variable X-chromosome random inactivation (XCI) in females, the phenotypic spectrum of the disease spans from milder forms—which include the possibility of autonomous walking and less severe epilepsy that is amenable to control—to severe forms featuring intractable seizures, more severe microcephaly and the absence of motor milestones
Since dendritic spine structure is fundamental for synaptic contact maintenance, we further evaluated the number of immunoreactive puncta for PSD-95 in the molecular layer of the hippocampal dentate gyrus of heterozygous and homozygous Cdkl5 female mice

Summary

Introduction

Cyclin-dependent kinase-like 5 (CDKL5) disorder (OMIM no. 300203) is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 gene. 300203) is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 gene. Primary clinical features include early-onset intractable epileptic seizures, gross motor impairment, severe intellectual disability, and autistic-like features [1,2,3,4]. Due to the different CDKL5 mutations and the variable X-chromosome random inactivation (XCI) in females, the phenotypic spectrum of the disease spans from milder forms—which include the possibility of autonomous walking and less severe epilepsy that is amenable to control—to severe forms featuring intractable seizures, more severe microcephaly and the absence of motor milestones. Boys carrying mutations in CDKL5 are much rarer and show more severe epileptic encephalopathy than girls [6, 7], probably due to the more severe consequences of dominant X-linked mutations in males than in females. CDKL5 is mainly expressed in neurons and is distributed in the cell nucleus and cytoplasm, as it shuttles between these cellular

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