Search

High-frequency oscillations (HFOs, ripples 80–250 Hz, fast ripples 250–500 Hz) are biomarkers of epileptic tissue. They are most commonly observed over areas generating seizures and increase in occurrence during the ictal compared to the interictal period. It has been hypothesized that their rate correlates with the severity of epilepsy and seizure in affected individuals. In the present study, it was aimed to investigate whether the HFO count mirrors the observed behavioral seizure severity using a kainate rat model for temporal lobe epilepsy. Seizures were selected during the chronic epilepsy phase of this model and classified by behavioral severity according to the Racine scale. Seizures with Racine scale 5&6 were considered generalized and severe. HFOs were marked in 24 seizures during a preictal, ictal, and postictal EEG segment. The duration covered by the HFO during these different segments was analyzed and compared between mild and severe seizures. HFOs were significantly increased during ictal periods (p < 0.001) and significantly decreased during postictal periods (p < 0.03) compared to the ictal segment. Ictal ripples (p = 0.04) as well as fast ripples (p = 0.02) were significantly higher in severe seizures compared to mild seizures. The present study demonstrates that ictal HFO occurrence mirrors seizure severity in a chronic focal epilepsy model in rats. This is similar to recent observations in patients with refractory mesio-temporal lobe epilepsy. Moreover, postictal HFO decrease might reflect postictal inhibition of epileptic activity. Overall results provide additional evidence that HFOs can be used as biomarkers for measuring seizure severity in epilepsy.

The work of this thesis aims to apply modeling and simulation techniques to mechanisms underlying neuronal activity, in order to promote drug discovery for the treatment of nervous system diseases. The models are developed and integrated at different scales: 1) the so-called "elementary models" permit to simulate dynamics of receptors, ion channels and biochemical reactions in intracellular signaling pathways; 2) models at the neuronal level allow to study the electrophysiological activity of these cells; and 3) microcircuits models help to understand the emergent properties of these complex systems, while maintaining the basic mechanisms that are the targets of pharmaceutical molecules. After a bibliographic synthesis of necessary elements of neurobiology, and an outline of the implemented mathematical and computational tools, the manuscript describes the developed models, as well as their validation process, ranging from the neurotransmitter receptor to the microcircuit. Moreover, these developments have been applied to three studies aiming to understand: 1) pharmacological modulation of the long-term potentiation (LTP) of glutamatergic synapses in the hippocampus, 2) mechanisms of neuronal hyperexcitability in the mesial temporal lobe epilepsy (MTLE), based on in vitro and in vivo experimental results, and 3) cholinergic modulation of hippocampal activity, particularly the theta rhythm associated with septo-hippocampal pathway.; Les travaux de cette thèse ont pour but de mettre en œuvre des outils de modélisation et de simulation numériques de mécanismes sous-tendant l’activité neuronale, afin de promouvoir la découverte de médicaments pour le traitement des maladies du système nerveux. Les modèles développés s’inscrivent à différentes échelles : 1) les modèles dits « élémentaires » permettent de simuler la dynamique des récepteurs, des canaux ioniques, et les réactions biochimiques des voies de signalisation intracellulaires ; 2) les modèles de neurones permettent d’étudier l’activité électrophysiologique de ces cellules ; et 3) les modèles de microcircuits permettent de comprendre les propriétés émergentes de ces systèmes complexes, tout en conservant les mécanismes élémentaires qui sont les cibles des molécules pharmaceutiques. À partir d’une synthèse bibliographique des éléments de neurobiologie nécessaires, et d’une présentation des outils mathématiques et informatiques mis en œuvre, le manuscrit décrit les différents modèles développés ainsi que leur processus de validation, allant du récepteur de neurotransmetteur au microcircuit. D’autre part, ces développements ont été appliqués à trois études visant à comprendre : 1) la modulation pharmacologique de la potentialisation à long terme (LTP) dans les synapses glutamatergiques de l’hippocampe, 2) les mécanismes de l'hyperexcitabilité neuronale dans l'épilepsie mésio-temporale (MTLE) à partir de résultats expérimentaux in vitro et in vivo, et 3) la modulation cholinergique de l'activité hippocampique, en particulier du rythme thêta associé à la voie septo-hippocampique.