Despite the availability of a wide range of antiepileptic drugs, in about one third of people who suffer from epilepsy, seizures cannot be adequately controlled by pharmacotherapy. The mechanisms... Show moreDespite the availability of a wide range of antiepileptic drugs, in about one third of people who suffer from epilepsy, seizures cannot be adequately controlled by pharmacotherapy. The mechanisms underlying this pharmacoresistance are still unclear. This thesis investigates the relationship between the time course of epileptogenesis, the associated changes in GABA mediated inhibition and the development of pharmacoresistance. Impairment of GABA, the brain's major inhibiting neurotransmitter, may lead to excessive activation of excitatory neuronal circuits, as is the case in epilepsy. In vivo studies using an animal model for epilepsy show that the GABA(A) receptor changes early in the epileptogenic process. Alterations include decreased expression and altered subunit composition, resulting in a receptor that is less sensitive to some ligands and more sensitive to others. Show less
Migraine has a strong genetic component, but the identification of these factors has proven difficult mainly because of the complex interaction of multiple loci and environmental factors.... Show moreMigraine has a strong genetic component, but the identification of these factors has proven difficult mainly because of the complex interaction of multiple loci and environmental factors. Unraveling its molecular basis and deciphering pathways leading to migraine attacks will help identifying novel treatment targets. For this thesis different genetic approaches were applied. Families with hemiplegic migraine (FHM), a rare monogenic subtype of migraine, were studied. Three genes were identified, all involved in modulation of ion influxes across neuronal and glial cell membranes. We identified many mutations in these genes and performed assays in cellular models to understand their functional consequences. In addition, we investigated the role of these genes in sporadic hemiplegic migraine (SHM). Importantly, we expanded the clinical spectrum associated with FHM genes, and established the link between migraine and epilepsy. We also performed genetic studies in common migraine families using two different approaches; the first was an outbred linkage approach with MO families, the second a family-based association approach with severe MA patients from a genetic isolate. Our results supported that, most likely, the intrinsic genetic heterogeneity in migraine families seriously hampers the identification of migraine loci and ultimately migraine genes. Show less