Exploring the role of circadian rhythms in CDKL5 deficiency disorder

CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by mutations in the CDKL5 gene and characterized by epilepsy, motor and visual impairments, hand stereotypies and sleep disturbances. The causes of sleep disfunctions in CDD are still unknown, a mechanism potential involved could be alterations in circadian rhythms. The aim of this project is to analyse circadian-rhythms and to investigate their potential role in a CDD mouse model, from both a functional and molecular point of view. Through thermographic recordings, we assessed daily rhythmicity in body temperature and locomotor activity in CDKL5 KO mice and their WT littermates over a period of seven days. We observed that CDKL5 KO mice show a significant increase in locomotor activity and body temperature during the transition between the light, resting phase and the dark active phase and viceversa. The observed changes prompted us to explore clock function in the brain. RNA sequencing from the hippocampus and the SCN revealed a gain in the number of genes that exhibit oscillatory expression in KO mice in both SCN and hippocampus, including some CDKL5 targets. Notably, the CDKL5 KO de novo oscillating transcripts displayed a specific phase of oscillation and belonged to specific gene ontology annotations. We revealed a dysregulation in circadian clock functions of CDKL5 KO mice, which could lead to a better understanding of CDD pathophysiology, and pave the way for novel therapeutic strategies.