This proposal addresses the regulation of M-currents by stargazin, and its impairment in human neurons and knock-in mice expressing stargazin variants associated with neurodevelopmental disorders.
The high comorbidity of epilepsy and neurodevelopmental disorders likely results from shared mechanisms. Forty percent of intellectual disability patients suffer from epilepsy, and individuals with schizophrenia have twice increased risk of developing seizures. Therefore, understanding the mechanistic pathways that link neurodevelopmental disorders and epilepsy is instrumental in developing more effective therapies. We found that M-channels, which are responsible for shaping neuronal excitability and firing, are regulated by stargazin, a protein encoded by the CACNG2 gene which is mutated in intellectual disability and schizophrenia patients. We will use human neuronal models and mice expressing the disease-related stargazin mutations to investigate how stargazin regulates M-channels, and whether this mechanism is disturbed in our models of disease, leading to increased seizure susceptibility. These models will also be used to test therapies to ameliorate the epileptic phenotype.