Our results suggest that CDKL5, through its interaction with the inhibitory scaffolding complex containing gephyrin and CB, regulates membrane levels of synaptic γ2-containing GABAARs. Deranged GABAAR levels are frequently linked to cognitive deficits and epilepsy, and we speculate that our results may help in explaining the seizure phenotype observed in CDD patients. This evidence concerns the gene GPHN and craniodiaphyseal dysplasia.