Genetic models of absence epilepsy: New concepts and insights

The discovery, development, and use of genetic rodent models of absence epilepsy have led to a new theory about the origin of absence seizures. A focal zone has been identified in the peri-oral region of the somatosensory cortex in WAG/Rij and GAERS – the two most commonly used models – from which the seizure quickly spreads over the cortex and to the thalamus. Activity in the cortex leads to activity in the thalamus in the first 500 ms of a seizure, and other cortical and thalamic sites consistently lag behind this focal site. After the first 500 ms of a seizure, the thalamus and cortex form a complex oscillatory network, and time relations and spreading directions can switch in an unpredictable way. Pharmacological, neurophysiological, and immunocytochemical studies confirm the existence of a focal cortical zone. This finding has led to the identification of various new disease-related mechanisms in the cortex and thalamus involved in the pathogenesis of absence seizures. The availability of fertile, healthy, and genuinely epileptic animals has also led to studies of gene–environment interactions, the comorbidity of absence epilepsy with psychopathologies, and of the interaction of different seizure types. The issue of comorbidities is gaining interest since it has become clear that not only depression, but also schizophrenia and anxiety disorders, occur more often in epilepsy patients than in the non-epileptic population. In models with two different seizure types, such as amygdala kindled or audiogenic sensitive WAG/Rij's or GAERS, the interaction of various seizure types can be studied. Understanding this interaction is important given that many patients have mixed symptoms which are often difficult to treat.