FUNCTIONAL CONSEQUENCES OF MUTATIONS ASSOCIATED TO FAMILIAL HEMIPLEGIC MIGRAINE TYPE 1 AND MIGRAINE MECHANISMS

Migraine is a common, chronic disorder characterized by recurrent disabling headaches affecting more than 10% of the population, bearing great societal and personal costs. The World Health Organization ranks migraine as one of the 20 most disabling diseases. Despite recent progress, drug therapy remains unsatisfactory or ineffective for many patients. The development of new drugs is slowed by our poor understanding of the primary cause of migraine and its mechanisms. Familial hemiplegic migraine type 1 (FHM1) is a rare form of migraine with aura caused by mutations in a gene encoding a neuronal calcium channel that controls neurotransmitter release in the brain. Since the symptoms of FHM1 are similar to those of common migraine (for which the genes involved are unknown), the aim of our project is to study the mechanisms causing aura and headache in FHM1 and thus gain insights into the mechanisms of migraine and aid the development of much needed new drugs for migraine prevention and acute treatment. We will use as experimental system mice carrying mutations found in human FHM1 patients and shown to have an increased susceptibility to cortical spreading depression (CSD, a wave of neuronal excitation followed by depression spreading across the cortex); CSD is the phenomenon underlying migraine aura and also the likely main trigger of headache. We will study the mechanisms leading to increased susceptibility to CSD and the consequences of FHM1 mutations, migraine mediators and antimigraine drugs on the function of the trigeminal neurons whose activation initiates the headache.