Role of dysregulated astrocyte-GABAergic interneuron interactions in the control of seizures in monogenic models of epilepsy

Seizures are a common, invalidating symptom of genetic and acquired neurological diseases. Seizures occur without warning and have severe consequences. In the so-called catastrophic epileptic encephalopaties of infancy, seizure recurrence cause progressive brain damage associated to neurologic and cognitive deficits. In spite of countless studies on the topic, the mechanisms that initiate and sustain a seizure are still not well understood. During a recent project funded by Telethon, we proposed a new mechanism for seizure onset. We demonstrated that two types of cells, astrocytes and neurons, cooperate to enhance brain excitability and promote seizure initiation. These findings rank astrocytes, once considered as scaffold cells, as mayor players in generation of brain activity in normal and diseased brains. Because inhibitory interneurons regulate neuronal network excitability and control epileptic discharges, it is important to clarify whether astrocytes affect activity of interneurons and how eventually this action contributes to epileptogenesis. We will test this main hypothesis in two mouse models of monogenic neurological diseases associated with seizures. In one of the model that reproduces a catastrophic child encephalopathy, the severe myoclonic epilepsy of infancy, the specific role of astrocyte-interneuron interactions in seizure generation and maintenance will be verified. The familial hemiplegic migraine is the only monogenic neurological disease associated with seizures due to a genetic defect restricted to astrocytes. The role of this specific astrocytic dysfunction in triggering seizures in a mouse model will be analysed using the most advanced techniques in neurobiological research. Our preclinical study will help to verify the pathogenic role of astrocytes in genetic epilepsies. The expected findings will set the basis to develop new remedies for epilepsies, both genetic and acquired, that are not cured by currently available treatments.