Étude de la dysfonction astrocytaire dans un modèle murin de syndrome de démyélinisation osmotique

Promoter

Prof. Charles NICAISE, UNamur, Molecular Physiology Research Unit (URPhyM), Laboratory Neurodegeneration and Regeneration (LNR)

Jury

Prof. Olivier De Backer (UNamur) - président du jury, Prof. Guy Decaux (Université Libre de Bruxelles), Prof. Aleksandar Jankovski (UCLouvain), Prof. Marie-Cécile Nollevaux (UCLouvain et UNamur), Prof. Patricia Renard (UNamur), Prof. Charles Nicaise (UNamur) - promoteur

Summary

Osmotic demyelination syndrome (ODS) is a neurological complication observed in alcoholic patients or after a rapid correction of chronic hyponatremia. Patients present several neurological symptoms depending on the localization of demyelinating lesions. Despite this demyelination, axons and neurons are relatively well spared. To unravel physiopathology of this syndrome we characterized temporally a mouse model mimicking human ODS. Mice presented neurological symptoms and demyelinating lesions in thalamic and pontine nuclei, cortex and inferior colliculus. Demyelinating lesions were significantly quantified beginning at 48 hours after the correction. At 24 hours after the correction a significant decrease of several oligodendrocytes (APC and p25α) and astrocytes (Aldh1L1, Cx43, S100b, AQP4) markers was observed in thalamus, along with changes of microglial cells morphology. Ultrastructural analysis of thalamic macroglial cells revealed that this decrease of immunoreactivity was not linked to cellular death. Indeed, only a few cells were presenting signs of necroptosis at 48 hours post-correction. Intra-cytoplasmic aggregates were notified in astrocytes already during the hyponatremia phase and were still present at 48 hours after the correction. These aggregates of undetermined content were present in astrocytes soma but also in perivascular end-feets which could be implicated in the blood-brain barrier dysfunction quantified at 48 hours after the correction. Our ultrastructural analysis did not permit us to observe any morphological modifications of endothelial cells composing this barrier. Next, we sought to compare the transcriptomes (by RNAsequencing) of astrocytes isolated from the thalamus and from the caudate putamen (ODS-resistant region) during normonatremia, chronic hyponatremia et six hours after the correction of chronic hyponatremia. This analysis between caudate putamen and thalamus during chronic hyponatremia revealed a downregulation of several genes implicated in the mitochondrial homeostasis such as mitochondrial ribosomal proteins or subunits of the complex I of oxidative phosphorylation. When we compared transcriptomes of thalamic astrocytes during normonatremia and chronic hyponatremia, we noticed a downregulation of genes implicated in the endoplasmic reticulum overload response in chronic hyponatremia. Two genes implicated in GABA transport were also significantly downregulated in thalamus during chronic hyponatremia and at six hours after the correction. These results point out that thalamic astrocytes could be early implicated in ODS development in mice.