CDKL5-mediated developmental tuning of neuronal excitability and concomitant regulation of transcriptome

Cyclin-dependent kinase-like 5 (CDKL5) is a serine-threonine kinase enriched in the forebrain to regulate neuronal development and function. Patients with CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition caused by mutations of CDKL5 gene, present early-onset epilepsy as the most prominent feature. However, spontaneous seizures have not been reported in mouse models of CDD, raising vital questions on the human-mouse differences and the roles of CDKL5 in early postnatal brains. Here, we firstly measured electroencephalographic (EEG) activities via a wireless telemetry system coupled with video-recording in neonatal mice. We found that mice lacking CDKL5 exhibited spontaneous epileptic EEG discharges, accompanied with increased burst activities and ictal behaviors, specifically at postnatal day 12 (P12). Intriguingly, those epileptic spikes disappeared after P14. We next performed an unbiased transcriptome profiling in the dorsal hippocampus and motor cortex of Cdkl5 null mice at different developmental timepoints, uncovering a set of age-dependent and brain region-specific alterations of gene expression in parallel with the transient display of epileptic activities. Finally, we validated multiple differentially expressed genes, such as glycine receptor alpha 2 and cholecystokinin, at the transcript or protein levels, supporting the relevance of these genes to CDKL5-regulated excitability. Our findings reveal early-onset neuronal hyperexcitability in mouse model of CDD, providing new insights into CDD etiology and potential molecular targets to ameliorate intractable neonatal epilepsy.

Automated summary

Cyclin-dependent kinase-like 5 (CDKL5) is an important regulator in neuronal development and function. Patients with CDKL5 deficiency disorder (CDD) often present with early-onset epilepsy. However, mouse models of CDD have not shown spontaneous seizures. In this study, the researchers found that mice lacking CDKL5 exhibited spontaneous epileptic EEG discharges at postnatal day 12, but these spikes disappeared after postnatal day 14. Transcriptome profiling revealed age-dependent and brain region-specific alterations of gene expression. These findings provide new insights into the etiology of CDD and potential targets for the treatment of neonatal epilepsy.