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Dépression Corticale Envahissante : nouveau mécanisme d'initiation par hyperactivité des neurones GABAergiques, et stratégie pharmacologique pour la réduire

Abstract : Cortical Spreading Depression is a wave of neuronal depolarization that spread slowly across cerebral cortex. It generates a rapid phase of neuronal hyperactivity, followed by a slower phase of electrical silence of cortical cells. It is possible to experimentally induce CSD on several animal models, in vivo or on neocortical slices, by focal application of Glutamate, Acetylcholine or highly concentrated KCl solution, or by electrical stimulation.CSD is widely studied as the pathophysiological mechanism of migraine with aura, but also ischemia. Studies of experimental CSD have shown involvement of numerous biological substances in the wave generation and propagation, including Potassium, Calcium, Glutamate, and other neurotransmitters. The pharmacological approach allows to identify actors of this electrical phenomenon: voltage gated channel, ionotropic glutamate receptors (NMDA & AMPRA-kainate), astrocytes and Na-K pumps.Familial Hemiplegic Migraine is a monogenic form of migraine with aura; the migraine attack is associated with variable motor disorders. Genetic mutations have been described leading to molecular dysfunctions. Nowadays three main forms of this pathology caused by three mutated genes, have been described and studied. FHM type 1 (Cav2.1 gain of function) and FH% type 2 (NaK ATPase pump loss of function) mouse models studies confirmed the important involvement of Glutamate and Potassium in CSD initiation.Type 3 of FHM is caused by Nav1.1 mutations, a voltage gated sodium channel that is widely expressed in GABAergic neurons in which they are essential for excitability. Our team showed on transfected neurons in culture that he mutation is a gain of function, leading to an increased neuronal excitability. However, the link between the mutation, cortical hyperexcitability and CSD facilitation or FHM phenotype, remains unknown.Our work hypothesis and the base of my research project, is that the increasing Nav1.1 channel or GABAergic neurons’ activity, triggers a cortical hyperexcitability and CSD. To confirm this hypothesis, my work required a ex vivo experimental approach, on acute neocortical slices of wild-type and transgenic mice, associated with extracellular electrophysiology, IOS imaging, pharmacology and/or optogenetics. Nav1.1 channel activation by a selective activator (spider toxin), or GABAergic neurons stimulation by optogenetics, can trigger CSD, validating our initial hypothesis and identify a new model of CSD.My work allow us to highlight and characterised a new model of CSD by GABAergic neuron hyperexcitability leading to an initial build up of extracellular potassium, that depolarizes and activates more and more excitatory neurons. This leads to a sustained potassium release until a critical threshold of CSD triggering.In a second time, my thesis work explored a pharmacologic modulation of network excitability, to find new elements that could decrease the CSD susceptibility. To do so, with the same experimental approach, I used a cholinergic agonist, Carbachol, known for modulation the network activity. The results showed that even if Carbachol increases network excitability, it inhibits CSD induction, likely through the muscarinic pathway.In conclusion, during my thesis I identified a new mechanism of CSD induction, and a une inhibitory pathway of CSD by cholinergic modulation.
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Sarah Zerimech. Dépression Corticale Envahissante : nouveau mécanisme d'initiation par hyperactivité des neurones GABAergiques, et stratégie pharmacologique pour la réduire. Biologie cellulaire. COMUE Université Côte d'Azur (2015 - 2019), 2019. Français. ⟨NNT : 2019AZUR4032⟩. ⟨tel-02617971⟩

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