Mechanisms of ictogenesis in an experimental model of temporal lobe seizures

Epilepsy is not a single disorder, but presents with a surrounding of symptoms that are not always of immediate identification and classification. About 50 million people worldwide have epilepsy. Seizures are more likely to occur in young children, or people over the age of 65 years. The mainstay of treatment of epilepsy is preventive anticonvulsant medication with anti epileptic drugs (AED). Despite the proven efficacy of most of these drugs, it is estimated that over 30% of people with epilepsy do not reach complete seizure control, and this category of patients is eligible for surgical therapy. Among them, people suffering from focal seizure and in particular temporal lobe epilepsy are candidates for surgery. In recent years, surgical ablation of the epileptogenic focus has been rewarded as the best way to cure seizures in patients with intractable focal epilepsy. Diagnostic scalp and intracranial stereo-EEG recordings can provide direct information from the epileptogenic focus and surrounding areas in order to circumscribe the zone to be surgically removed. Data obtained from the analysis of the patients' EEG brought to the identification of specific ictal patterns which in turn helped to better classify the already clinically defined seizure types. These patterns can be reproduced in animal models of epilepsy and/or seizures. Focal seizures in the temporal lobe of the isolated in vitro guinea pig brain can be induced by perfusion of proconvulsant drugs. The electrophysiological recordings from the limbic structures of this animal model inform about the mechanisms leading to seizure onset (ictogenesis) and their progression. These phenomena are being studied both from a neuro-physiological and functional point of view; also histology and other anatomo-functional techniques give us a global idea of the activities occurring in different brain compartments during seizure-like events. The ultimate goal of this research will be to further clarify the causes for which a focal seizure is generated and the regulatory mechanisms that govern the different patterns similar to those identified in humans. Intracellular recordings from principal neurons in the superficial and deep layers of the entorhinal cortex showed a different involvement of these two regions in seizure initiation and development. We demonstrate that at seizure onset there is a strong activation of GABAergic interneuron (Gnatkovsky et al., 2008). This finding points to a primary role of GABAergic inhibition in seizure generation. We further showed that slow potentials recorded during the first steps of ictal activity are a typical sign of modifications of ionic composition of the extracellular medium and describe very well the shape of low voltage shifts with fast activity (Trombin et al., in preparation). Spikes shape identified by intracellular recordings during seizures was also analyzed to evaluate the epileptogenic network. The correlation of AP changes during seizures with the field potential and the increase in extracellular [K] clearly indicates both neuronal and non-neuronal processes, take place during the initiation and the termination of a seizure (Trombin et al, in preparation). Taken together all these data point out a multi-factorial scenario in which inhibitory networks play a crucial role in seizure generation, in association with changes in glial function and extracellular homeostasis. The impairment of one of these elements can be a triggering event in the development of seizures (ictogenesis), and can start in turn a cascade of permanent modifications that maintain an hyper-excitability condition, leading to epileptogenesis. The precise knowledge of each passage needed to transform a normal tissue into an epileptogenic one is a fundamental achievement in order to recognize and classify the different syndromic manifestations of epilepsy. Further, the possibility to interfere with one of the above mentioned processes is of evident relevance for the modulation of seizure beginning and establishment.