GABAA-receptor defects in CDKL5 deficiency disorder: molecular mechanisms and targeting by synthetic neuroactive steroids

CDKL5 deficiency disorder (CDD) is a neurological disorder characterized by early-onset epilepsy, intellectual disability, and autistic features. A full understanding of the neuropathological bases of CDD and the development of therapeutic strategies is challenged by our limited knowledge of CDKL5 functions. Mouse models of CDD recapitulate most features of the human disorder making them a valuable tool to study the basis of CDD and to test drug-based therapies. We have gathered strong evidence indicating that CDKL5 potently affects GABA_A-receptor (GABA_AR) mediated inhibitory neurotransmission. GABA_ARs constitute an important molecular target for drug-based therapies against epilepsy, cognitive dysfunctions and autism, underscoring the relevance of promptly analyzing further this aspect in CDD. With this project, we will use complementary approaches to study the role of CDKL5 in controlling the proper functioning of GABA_ARs in a CDD mouse model and in human post-mortem brains paying attention on the involved molecular mechanisms. Importantly, we will also test the possibility of the drug-based restoration of inhibitory neurotransmission in CDD-models. Altogether, we are firmly convinced that this ambitious project will advance significantly the understanding of CDKL5 functions through the characterization of its previously unexplored role in GABAergic synaptic inhibition. Importantly, the exploration of phenotypic rescue may open to novel therapeutic avenues for CDD.