BENIGN FAMILIAL NEONATAL CONVULSIONS AND THE M-CURRENT: FROM MUTATIONAL ANALYSIS OF KCNQ2/3 GENES TO THE MOLECULAR MECHANISMS OF NEUROTRANSMITTER RELEASE AND VOLTAGE SENSING IN POTASSIUM CHANNELS

Epilepsy affects 0.5-1% of the general population, representing a major burden for affected individuals, their families, and the whole society; understanding the genetic, biochemical, and functional mechanisms causing epilepsy is therefore a major human health issue. Most epilepsies do not recognize a specific triggering mechanism or an hereditary transmission; however, a small fraction (1-2%) of epilepsies are genetically-determined. Within these hereditary forms, Benign Familial Neonatal Convulsions (BFNC) have a typical onset in the first week of postnatal life and end spontaneously by the age of three-six months. The genetic basis of most hereditary forms of epilepsies, including BFNC, have been identified, leading to the concept that a altered function of ion channels (membrane proteins controlling the flux of specific classes of ions across the plasmamembrane of neurons and other excitable cells) can lead to the neuronal hyperexcitability underlying epilepsy. Therefore, a pressing current interest is the understanding of how such genetic alterations disturb the electrical activity of the brain, and how such altered excitability triggers the convulsive phenotype. The present research project, which will be carried out by an established multidisciplinary team of clinical and basic researchers, aims to solve some crucial issues in the epilepsy field. The achievement of the proposed aims, by furthering our understanding of the intimate molecular mechanisms of operation and of the functional role of a specific class of ion channels, will improve knowledge about the pathogenesis of BFNC, and will lead to the development of novel therapeutic approaches in epileptic patients, 25% of whom do not receive satisfactorily treatment.