The functional role of CDKL5 at the inhibitory synapse and its interaction with the cytoplasmatic collybistin-gephyrin complex

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) are responsible for a severe neurodevelopmental disorder, namely CDKL5 deficiency disorder (CDD), characterised by early-onset epileptic encephalopathy, severe intellectual disability and intractable seizures. So far, the role of CDKL5 in excitatory synapses has been widely explored; on the contrary, more has still to be investigated regarding its influence on the inhibitory compartment. Our recent data showed that CDKL5 loss impacts the number of synaptic GABAARs, which may be explained by its interaction with the postsynaptic scaffolding complex containing gephyrin (GPHN) and collybistin (CB). GPHN is the core scaffolding protein of the inhibitory synapse, while CB is a brain specific GEF, involved in GPHN recruiting to postsynaptic sites. CB is retained in a folded-inactive conformation by its auto-inhibitory SH3 domain; when this domain interacts with other proteins, CB switches in the open-active conformation. Interestingly, through various biochemical and immunofluorescence approaches based on different derivatives of both proteins, we have demonstrated that CDKL5 can release CB from its inactive conformation allowing the distribution of GPHN to sub-membranous sites in expressing cells.