NICOTINIC ACETYLCHOLINE RECEPTORS AND NOCTURNAL FRONTAL LOBE EPILEPSY

Epilepsy is a common neurological disorder. It is due to temporary uncontrolled hyperactivity of the electrical signaling in the brain (a so-called seizure). Seizures during light sleep are clinical symptoms of a nocturnal form of epilepsy, the Nocturnal Frontal Lobe Epilepsy. Recent work suggests that malfunction of the brain receptors for acetylcholine is one of the most common causes of the disease. These receptors are very big protein molecules located within the membrane of the neurons. After acetylcholine binding, they change their conformation, opening a pore that allows an ion current to flow across the cell membrane. This triggers the electrical signaling in the brain cells. The pore subsequently closes (desensitizes) to terminate the response. When the acetylcholine receptor is mutant, the current flow may be either blocked or increased. Depending on the location of the different acetylcholine receptors, both effects may produce neuron hyperexcitability, thus causing epilepsy. We shall study one of the genes known to be responsible for the nocturnal epilepsy, the ENFL3. This gene codes for one of the subunits which compose the complete acetylcholine receptor, the beta2 subunit. We have found that a specific mutation in this gene produces an acetylcholine receptor which closes very slowly compared to the normal receptors, thus altering the normal nervous transmission. However, the precise mechanism through which the mutation produces epilepsy is not fully understood, yet. We shall pursue this goal by using molecular and electrical techniques. We shall study in detail the properties of the mutant receptors in cellular models and in animal models. This will lead to a better understanding of nocturnal epilepsy. Moreover, we shall study whether the mutant channels responds to pharmacological agents in a different way, which may lead to therapeutic applications. We shall also continue to screen patients, to find new mutations of the same kind.