Neuronal nicotinic receptors in sleep-related epilepsy: studies in integrative biology

Although Mendelian diseases are rare, when considered one by one, overall they constitute a significant social burden. Besides the medical aspects, they propose us one of the most general biological problems. Given the simplest physiological perturbation of an organism, that is, a single gene mutation, how do its effects percolate through the hierarchical biological levels to determine the pathogenesis? And how robust is the physiological system to this perturbation? To solve these problems, the study of genetic epilepsies caused by mutant ion channels presents special advantages, as it can exploit the full range of modern experimental methods. These allow to extend the functional analysis from single channels to whole brains. An instructive example is autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), which can be caused by mutations in neuronal nicotinic acetylcholine receptors. In vitro, such mutations often produce hyperfunctional receptors, at least in heterozygous condition. However, understanding how this leads to sleep-related frontal epilepsy is all but straightforward. Several available animal models are helping us to determine the effects of ADNFLE mutations on the mammalian brain. Because of the complexity of the cholinergic regulation in both developing and mature brains, several pathogenic mechanisms are possible, which also present different therapeutic implications.