Spatio-temporal firing dynamics of cortical and thalamic neurons during typical absence seizures

Absence epilepsy is different from the popular image of epilepsy, since its seizures are not accompanied by convulsions or other major motor and behavioural signs. In its milder forms, in fact, an absence seizure may simply consists of a sudden and brief interruption of consciousness (i.e. the sufferer appears to be ?absent? from surrounding activities) and some minor facial, arm or leg movements, explaining why almost up to the middle of the last century this disease went largely undetected and often unrecognized as a proper neurological disease. Absence epilepsy is a genetic condition that can occur in children as young as 2 years of age. In milder cases, seizures may spontaneously disappear in the late teens, but in the vast majority of severe cases they can occur up to 200 times per day, and are accompanied, or develop into, convulsive epilepsy. Whereas there are medicines capable of abolishing or reducing the daily frequency of absence seizures, their use is not effective in all sufferers, is associated with a number of unwanted side-effects (particularly in children), and is not advisable in women of child-bearing age. While pro-active counselling of partners from families with a history of absence seizures has been welcome worldwide, our ability to cure this disease, and thus to reduce its educational, developmental and financial burden, is compounded by the large number of different genetic mutations that are responsible for this disease and by our poor understanding of the intricate brain alterations that lead to the expression of these seizures. This project, will aim to characterize the way communications between different types of specialized cells in the brain (called neurons) alter their electrical activities during absence seizures. We will focus on two areas of the brain (called the cortex and the thalamus) that have been shown by non-invasive imaging of epileptic patients to be the key regions where absence seizures originate. Moreover, we will investigate whether the passage of calcium ions through specific pores in these neurons is of importance for setting in motion the abnormal electrical events that lead to absence seizures. This research will potentially lead to novel avenues of therapeutic intervention for absence seizures, and partly fill the gap left by the lack of support from the private sector due to the small size of the market for novel drugs for this disease compared to the neurological disorders of old age.

A typical absence is a non-convulsive epileptic seizure characterized by a sudden and relatively brief impairment of consciousness, occurring concomitantly with a generalized and bilaterally synchronous ?(poly)spike and slow wave discharge? (SWD) paroxysm at 2.5-4 Hz in the EEG. Typical absence seizures are part of the complex clinical and EEG presentation of a large number of idiopathic generalized epilepsies, and there is a general consensus on the key involvement of reciprocally connected thalamic and cortical networks in the generation of these seizures. Their pathophysiological mechanisms, however, are still not fully understood. Taking advantage of recent developments in neuronal ensemble recordings and the availability of potent and specific T-type calcium channel antagonists, here we propose i) to characterize the spatial and temporal dynamics of the firing of large neuronal populations in reciprocally connected cortical and thalamic territories during experimental absence seizures, and ii) to investigate the role that cortical and/or thalamic T-type calcium channels play in the generation of these epileptic events. To overcome long-standing controversial issues in this field, our work will be carried out in freely moving animals, will use rat and mouse, genetic and pharmacological models of absence seizures, and will critically correlate the electrographic and the behavioural components of the seizures. By elucidating the essential participation of different neuronal assemblies in absence seizures generation, and the brain area/nucleus-specific involvement of T-type calcium channels, our results will provide novel potential avenues of therapeutic intervention for this type of epilepsy.