Longitudinal analysis of age-dependent phenotypes in hemizygous male and heterozygous female Cdkl5 mutant mice

Abstract

Mutations in cyclin-dependent kinase-like 5 (CDKL5) gene trigger a severe neurodevelopmental disorder marked by motor impairment, intellectual disability, autistic-like behaviors, and early-onset epilepsy. Although several Cdkl5-deficient animal models mimic key aspects of the human condition, including hyperactivity and behavioral abnormalities, compromised neuronal architecture and connectivity, and altered activity-dependent synaptic plasticity they fall short of providing a unified understanding of the disorder's cellular and molecular underpinnings. These inconsistencies likely stem from variations in the analyzed brain regions, differences in the ages, sexes and genetic backgrounds of experimental subjects. In this study, we focus on characterizing distinct phenotypes, i.e. activity-dependent synaptic plasticity, hippocampal dendritic spine density, and behavior and provide a longitudinal study of their temporal evolution and sex/genotype-specific patterns. Our findings reveal that in both male and female Cdkl5 deficient mice, disruptions in synaptic plasticity and changes in dendritic spine density develop dynamically in an age-, region- and hemisphere-dependent manner. Collectively, our results expand on previous observations by demonstrating how pathological phenotypes evolve in Cdkl5 mutant mice with age and differ between sexes. Given the absence of a cure and the limited treatment options, our work underscores the urgent need for a deeper understanding of Cdkl5 mutant phenotypes particularly including female subjects. This insight is crucial for the development of effective therapeutic strategies.