The role of neuronal nicotinic receptors in the pathogenesis of autosomal dominant nocturnal frontal lobe epilepsy: a study on wild-type and conditional transgenic mice expressing the beta2-V287L subunit

Epilepsy is a very common disorder of the brain, which affects about 50 million people throughout the World. Moreover, approximately 10% of the human population undergoes at least one epileptic fit during lifetime. The genetic forms of epilepsy are often caused by mutations on genes coding for ion channels. These are special proteins which control (among other functions) the electrical activity in the brain. Their alteration can lead to the development of epileptic seizures. Thus, "channelopathies"; are genetic diseases due to mutations in genes coding for ion channels. Many tenths of channelopathies are known to date and more and more are discovered each year. Studying the properties of the mutant channels in the proper patophysiological context is indespensable to understand the nature of the disease. Our project regards ion channels named neuronal nicotinic acetylcholine receptors (nAChRs) that, when mutated, lead to frontal lobe epilepsy during sleep. How these mutations cause the disease is still unclear, because the cerebral roles of nAChRs are complex and understood only in part. We will carry out physiological studies in the cerebral cortex of murine models of this disease, in order to determine how mutant receptors cause the disease. From a therapeutic standpoint, in this and other epileptic forms, about 30% of the patients are unresponsive to pharmacologic treatment. Unresponsivity may depend on stable circuit alterations occurring during development, which cannot be reversed by drug administration in the mature brain. Because antiepileptic drugs generally act by inhibiting ion channels, we will study how common antiepileptics as well as other ion channel modulating compounds affect the nAChR-dependent network stabilization during sensitive phases of brain development.