Implication des connexines gliales dans les atteintes de la Neuromyélite Optique : un rôle dans la démyélinisation et les altérations neuronales

Abstract : Neuromyelitis Optica (NMO) is a rare and severe auto-immune demyelinating disease of the central nervous system (CNS). It is characterized by demyelination and axonal loss targeted to the optic nerve dans the spinal cord. The identification of a specific autoantibody (NMO-IgG) directed against the astrocytic protein AQP4 was a key step in the understanding of NMO physiopathology: it is now considered as an astrocytopathy. NMO-IgG is also a biomarker of NMO, and its pathogenicity has been demonstrated. NMO-IgG induce an internalization of AQP4 together with other membrane proteins such à glutamate transport GLT1. This could alter astrocyte functions but the mechanisms connecting astrocytopathy and demyelination remain unclear. Astrocytes are abundant glial cells crucial for the establishment and the maintenance of CNS homeostasis. They regulate water flux and ion homeostasis and control extracellular volume and neurotransmitter concentrations. They also provide neurons and oligodendrocytes with energy substrates. Astrocytes are characterized by a high expression of connexins (Cx), transmembrane proteins assembling in hexameric form, called connexon. Cx form either hemichannels, unopposed connexon at the membrane, allowing the exchange of small molecules (<1,2kDa e.g. glutamate, ATP) and ions (Ca2+, K+) between extra- and intra-cellular compartments. Cx also form gap junctions, formed by the juxtaposition of two connexons at the membrane of two different cells, and allow the quick cell to cell exchange of small molecules, metabolites and ions (e.g. glucose, lactate, Ca2+). Hemichannel and gap junction functions are tightly regulated under physiological conditions and can be altered in pathological condition for example during neuroinflammation. We proposed that NMO-IgG by altering connexins expression and/or function could lead to the production of a toxic environment for oligodendrocytes and myelin but also for neuronal functioning. This feature of astrocyte dysfunction could participate to NMO alterations. My thesis project had three main goals: i) the characterisation of astrocyte phenotype induced buy NMO-IgG, ii) the identification of connexins alterations and their implication NMO physiopathology, iii) the highlight of synaptic alterations induced by NMO-IgG and the involvement of connexins in this effect. Primary glial cell cultures treated with NMO-IgG from a cohort of NMO patients, were used to characterize astrocyte phenotype and we proposed the concept of a specific reactive dysfunctioning astrocyte induced by NMO-IgG. Those astrocytes, called “NMO-astrocytes” are responsible for the production of a proinflammatory toxic microenvironment for oligodendrocytes and leading to demyelination. With the development of a myelinated culture model, composed of glial cells and neurons with myelinated axons, together with the use of specific inhibitors of Cx functions, we showed that NMO-IgG induced demyelination involved connexin dysfunction. In fact, demyelination was associated with structural and functional alterations of astrocytic connexins observed both in vitro and in vivo in the NMO-rat model. Electrophysiological recording of basal glutamatergic synaptic activity in the rat hippocampus showed a strong depression of synaptic responses induced by NMO-IgG. Connexins could be implicated in this alteration since blocking all connexins with carbenoxolone blocked NMO-IgG effect
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Chloé Richard. Implication des connexines gliales dans les atteintes de la Neuromyélite Optique : un rôle dans la démyélinisation et les altérations neuronales. Neurosciences [q-bio.NC]. Université de Lyon, 2019. Français. ⟨NNT : 2019LYSE1075⟩. ⟨tel-02276888⟩

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