PCDH19-related neurodevelopmental syndrome: unraveling the players of neuronal hyperexcitability in search of new therapeutic targets

Mutations in PCDH19 gene cause a neurodevelopmental disorder named Epileptic Encephalopathy, Early Infantile, 9 (EIEE9) that affects mainly girls and is characterized by seizures, autism and cognitive disabilities. PCDH19 encodes for a protein named protocadherin-19, which is normally expressed on the surface of neurons and allows them to interact with each other and form circuits. However, we found that protocadherin-19 can also exert an unexpected role in the nucleus, where it regulates the expression of some genes important for neuronal excitability and synaptic plasticity. Furthermore, it has been reported that in EIEE9 patients' skin cells the gene encoding the oxytocin receptor is dysregulated. Oxytocin is a neuropeptide important for cognitive and social behavior and is a promising treatment for neurodevelopmental disorders associated to autism and psychiatric features. Based on these premises, our goal is to identify, within the genome, all genes regulated by PCDH19 and to test the potential involvement of the oxytocin system in EIEE9 syndrome. We will exploit a mouse model of EIEE9 (the Pcdh19 KO mouse) and innovative technologies to discover which genes are regulated by protocadherin-19 in different types of neurons and at different stages of brain development in both males and females. Furthermore, we will study the oxytocin system in the Pcdh19 KO mouse and test whether it might benefit from the oxytocin treatment. With this project, we expect to provide a better understanding of EIEE9 syndrome and possibly identify new therapeutic targets and strategies to ameliorate EIEE9 patients’ condition.