Cdkl5 Knockout Mice Recapitulate Sleep Phenotypes of CDKL5 Deficient Disorder

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is an X-linked rare neurodevelopmental disorder associated with severe sleep disturbances. However, little is known about the mechanisms underlying sleep disturbances in CDD patients. Here, we employed the electroencephalogram (EEG) recording to characterize sleep-wake behaviors and EEG activity in male CDKL5-deficient mice. We found that young adult and middle-aged Cdkl5 knockout (KO) mice recapitulated sleep phenotypes in patients with CDD, including difficulties in initiating and maintaining sleep, reduction in total sleep time, and frequent night awakenings. Cdkl5 KO mice exhibited pre-sleep arousal, but normal circadian rhythm and homeostatic sleep response. Conditional knockout (cKO) of Cdkl5 in glutamatergic neurons resulted in reduced sleep time and difficulty in sleep maintenance. Further, the rate of age-associated decline in sleep and EEG activity in Cdkl5 KO mice was comparable to that of wild-type littermates. Together, these results confirm a causative role for CDKL5 deficiency in sleep disturbances observed in CDD patients and establish an animal model for translational research of sleep treatment in CDD. Moreover, our results provide valuable information for developing therapeutic strategies and identifying sleep and EEG parameters as potential biomarkers for facilitating preclinical and clinical trials in CDD.