Caratterizzazione di un nuovo ruolo di CDKL5 nella sinapsi inibitoria e utilizzo di una possibile strategia terapeutica per i difetti legati alla mancanza di CDKL5

Mutations in the cyclin-dependent kinase like 5 gene (CDKL5) have been found in individuals with a rare X-linked neurodevelopmental disorder, CDKL5 deficiency disorder (CDD), characterised by early-onset epilepsy, severe intellectual disability, drug-resistant seizures and infantile spasms. This disorder affects mostly females who are heterozygous for CDKL5 deficiency and mosaic for the mutated allele because of the random X-chromosome inactivation. No cure exists for patients with CDD and the development of rationally designed drug-based therapies is still extremely challenging due to the limited knowledge of CDKL5 functions. Although the role of CDKL5 at excitatory synapses is widely studied, a potential role of the protein in the specific regulation of the inhibitory neurotransmission has been rather neglected up until now. Therefore, this Ph.D. thesis aims at exploring a potential role of CDKL5 at the inhibitory synapse, focusing on the key component of this compartment to elucidate possible alterations in the absence of CDKL5. Based on our findings, we hypothesise that CDKL5 exerts a dual control on synaptic GABAAR expression: a direct regulation through its interaction with the gephyrin-CB-NL2 complex and an indirect effect through its control on MT dynamics. Future studies will aim at investigating the molecular composition of the inhibitory synapse and the role of CDKL5 in regulating the conformational switch of CB. Moreover, in agreement with the control of CDKL5 of MT dynamics, the pharmacological targeting of such dynamics seems to stabilise the postsynaptic sites and potentiate GABAAR functioning, constituting an important breakthrough in the CDD field.