Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) are responsible for a severe neurodevelopmental disorder, namely CDKL5 deficiency disorder (CDD), characterized by early-onset epileptic encephalopathy, intellectual disability, and intractable seizures. So far, the role of CDKL5 in excitatory synapses has been widely explored; conversely, 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, collybistin and neuroligin 2. Considering all the above, this project aims at exploring the potential role of CDKL5 in the inhibitory synapse, focusing the attention on the aforementioned scaffolding complex. Through co-immunoprecipitation and immunofluorescence approaches exploiting different derivatives of CDKL5 and collybistin, we find that CDKL5 can release collybistin from its inactive conformation allowing the distribution of gephyrin to sub-membranous sites in expressing cells and that the interaction requires the collybistin SH3 domain and the catalytic activity of CDKL5. We are currently investigating whether collybistin is phosphorylated in a CDKL5 dependent manner through the PhosTagTM approach. Moreover, through biochemical approaches we have found that CDKL5 regulates NL2 levels making us hypothesize a role of CDKL5 in regulating the interaction between collybistin-neuroligin. Altogether, these results seem to place CDKL5 as a novel key regulator of the postsynaptic scaffolding complex of inhibitory synapses. Elucidating synaptic networks regulated by CDKL5 may pave the way to comprehend the pathogenic mechanisms of CDD and to develop novel therapeutic approaches.