Behavioral impulsivity is associated with pupillary alterations and hyperactivity in CDKL5 mutant mice

Abstract

Cyclin-dependent kinase-like 5 (Cdkl5) deficiency disorder (CDD) is a severe neurodevelopmental condition caused by mutations in the X-linked Cdkl5 gene. CDD is characterized by early-onset seizures in the first month of life, intellectual disability, motor and social impairment. No effective treatment is currently available and medical management is only symptomatic and supportive. Recently, mouse models of Cdkl5 disorder have demonstrated that mice lacking Cdkl5 exhibit autism-like phenotypes, hyperactivity, and dysregulations of the arousal system, suggesting the possibility to use these features as translational biomarkers. In this study, we tested Cdkl5 male and female mutant mice in an appetitive operant conditioning chamber to assess cognitive and motor abilities, and performed pupillometry to assess the integrity of the arousal system. Then, we evaluated the performance of artificial intelligence models to classify the genotype of the animals from the behavioral and physiological phenotype. The behavioral results show that CDD mice display impulsivity, together with low levels of cognitive flexibility and perseverative behaviors. We assessed arousal levels by simultaneously recording pupil size and locomotor activity. Pupillometry reveals in CDD mice a smaller pupil size and an impaired response to unexpected stimuli associated with hyperlocomotion, demonstrating a global defect in arousal modulation. Finally, machine learning reveals that both behavioral and pupillometry parameters can be considered good predictors of CDD. Since early diagnosis is essential to evaluate treatment outcomes and pupillary measures can be performed easily, we proposed the monitoring of pupil size as a promising biomarker for CDD.

Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder

“…Importantly, the time spent in the center of the open-field arena did not differ between the groups, indicating that anxiety-like behavior did not bias the outcome of this motor test. Our study is the first to demonstrate that Cdkl5 KO mice show an increased exploratory impulsivity in reaction to objects in an open-field arena, but this finding is in accordance with a recent finding showing that Cdkl5 KO mice display an impulsive and hyperactive phenotype in an appetitive conditioning task [ 63 ]. We found a large inter-individual variability in the impulsive and hyperactive phenotype of Cdkl5 KO mice.…”

“…Recent studies demonstrated that mice lacking Cdkl5 exhibit hyperlocomotion and impulsivity, resembling core symptoms of attention-deficit hyperactivity disorder (ADHD) [ 60 , 61 , 62 , 63 ]. We found that voluntary running restored abnormal elevated locomotor activity (longer distance traveled, Figure 2 A, with a higher average speed, Figure 2 B) during the open-field exploration period in Cdkl5 −/Y mice.…”

A Comparative Machine Learning Study of Connectivity-Based Biomarkers of Schizophrenia

“…The CV and test performance across all classifiers and feature subsets was compared to two baselines, namely: Test performance on the PCA dataset (all 149 components) of the logistic regression. the dummy classifier which randomly picks the class for each sample. It is frequently used as a baseline in machine learning research 35,36 . Note that in this study the accuracy of the dummy classifier consistently remained at 73.7%. In contrast, the F1 score for this classifier is always 0, meaning that it does not differentiate between the two classes.…”

Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability

“…Instead, we suggest that the GoF of unphosphorylated Cav2.3 underlies the hyper-excitability seen in response to muscarinic stimulation. Interestingly, Cdkl5 KO mice have altered cholinergic tone 76 , 89 and the muscarinic antagonist Solifenacin was shown to ameliorate network defects in CDD patient-derived neurons 90 , supporting an enhanced cholinergic modulation in this human model.…”