Functional characterization of the InSyn1-CDKL5 interaction for dystrophin/dystroglycan complex dependent inhibitory synapse formation

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

CDKL5 disorder (CDD) is a rare genetic disorder characterized by early-onset drug-resistant epileptic encephalopathy, motor, cognitive, visual and autonomic disorders. CDD is caused by mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene and occurs with an incidence of 1 in 40,000 live births. Despite the efforts of the researchers, much remains to be elucidated about the role of CDKL5 in the central nervous system, which hinders the achievement of an effective therapy for CDD. The epileptic seizures and cognitive deficits that occur in CDD patients emphasize the importance of the protein in the correct regulation of neuronal activity, which is based on a complex balance between excitation and inhibition. While the part concerning excitation is currently under investigation in many laboratories, the function of CDKL5 at the inhibitory compartment remains largely unknown. In this regard, we have collected preliminary data demonstrating an interaction between CDKL5 and InSyn1, a protein that appears to be particularly important for the correct functioning of the inhibitory network. In particular, InSyn1 is able to regulate the function of a protein complex, called DGC, which serves for the formation of specific inhibitory neurons, essential for "turning off" and regulating the excitation that is generated physiologically by neurons. We hypothesize that the absence of CDKL5 can negatively affect the activity of InSyn1 and DGC by creating an imbalance in the neuronal activity. So with this project we want investigate what happens in the inhibitory compartment to InSyn1 and DGC when CDKL5 is missing. To do this we will use both cellular and animal models depleted of CDKL5. We believe that these aspects, never investigated before in the CDD field, represent an interesting step forward to clarify the role of CDKL5 in inhibitory circuits and to design more effective therapeutic strategies for CDD patients.