Ricerc@Sapienza

In different epileptic syndromes of childhood as tuberous sclerosis complex (TSC), a rare multi system genetic disease, focal cortical dysplasia type II (FCD II), and Rett syndrome, GABA shows a delay in the normal development, maintaining a less hyperpolarizing action, a typical feature of immature brain. Therefore, an unbalance of GABAergic and glutamatergic transmission can explain, at least in part, the high incidence of epilepsy in these patients. Other paediatric diseases that are characterized by the presence of refractory seizures, as Dravet and Angelman syndromes, could share with TSC and FCD a common feature of loss of GABAergic function. Our main goal, using electrophysiological and molecular approaches, is to study the GABAA and AMPA evoked currents in aforementioned human paediatric diseases, in order to suggest new therapies, that could consider not only the primary causes of the diseases, but also a broader scenario of an aberrant neurotransmission underlying epilepsy and the consequent cognitive impairment. We will use human cortical tissues from autopsies of refractory epileptic syndromes (Dravet, TSC, FCD, Rett, Angelman) and age-matched controls to study whether: (1) GABAA transmission is less inhibitory; (2) both AMPA and GABAA subunits expression maintain an immature profile; (3) new drugs could act on the altered neuro- transmission with low side-effects. We intend to demonstrate that a dysfunction of the GABAergic system can contribute to a general reduction of inhibitory efficacy in epileptic syndromes of childhood suggesting that GABAA receptors could be a target for new add-on therapies. Of note, an altered neurotransmission, as feature of brain immaturity, could also contribute to the observed cognitive impairment and intellectual disabilities.