Interactions neurogliales dans la physiologie et les pathologies cérébrales / Neuroglial interactions in cerebral physiology and pathologies
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Page web : https://www.college-de-france.fr/site/en-cirb/rouach.htm.
1The main goal our research is to determine whether and how the underexplored astrocytes, which are the very abundant non neuronal but yet active cells of the brain, play a direct role in information processing. We particularly explore the molecular modalities and functional outcomes of astrocyte-neuron interactions in various physiological or pathological contexts, such as memory or epilepsy, focusing ex vivo or in vivo on neuronal excitability, synaptic transmission, plasticity and synchronization, as well as on cognitive functions. To overcome the present conceptual and experimental difficulties in the field of neuroglial interactions, we have developed an innovative multidisciplinary approach combining electrophysiology, 2 photon and super-resolution imaging, behavioral testing, mathematical modeling, and new strategies and molecular tools targeting selectively astrocytes in mice and human tissues. Using this strategy, we primarily explored in the last year the role of astrocytes in neuronal network activity in normal and pathological conditions. In particular we explored the impact of several factors on neurotransmission, including (pannexin 1 (Px1) channels and Cx30-dependent mechanism as well as the role of Cx30 on astroglial plasticity during development.
2We found that Px1, a protein homolog to connexins and which forms membrane channels, controls seizure generation in human cortical post-operative tissues from epileptic patients and in a mouse model of temporal lobe epilepsy (Dossi et al., 2018). Px1 channels are indeed strongly activated in ictogenic condition and contribute to seizures by promoting and sustaining ictal activity. Such control occurs in tissues from epileptic patients with different pathologies and developmental profiles and is mediated by ATP release and activation of P2 receptors. These data suggest that Px1 may be a therapeutic target against various human epilepsies.
3We also recently revealed that Cx30, one of the two astroglial gap junction channel subunit, which is a determinant of astroglial synapse coverage controlling synaptic efficacy and hippocampal-based memory via an unprecedented non channel function controlling the astroglial coverage of synapses (Pannasch et al., 2014), also controls hippocampal neuronal population bursts and associated convulsive behavior (Pannasch et al., 2019). We report that Cx30 expression is increased in vivo by seizures and that it controls in turn the severity of behavioral seizures. The Cx30 modulation of neuronal network activity is mediated by regulation of astroglial glutamate uptake independently of gap junction mediated biochemical coupling. These data indicate that astroglial Cx30 plays a crucial role in orchestrating the activity of neuronal networks.
4Remarkably, we also found that Cx30 regulates the morphology and polarity of migrating astrocytes during postnatal development via its non-channel function (Ghézali et al., 2018). We indeed found that Cx30 sets the orientation of astroglial motile protrusions via modulation of the laminin/β1 integrin/Cdc42 polarity pathway. Connexin 30 indeed reduces laminin levels, inhibits the redistribution of the β1-integrin extracellular matrix receptors, and inhibits the recruitment and activation of the small Rho GTPase Cdc42 at the leading edge of migrating astrocytes. In vivo, connexin 30, the expression of which is developmentally regulated, also contributes to the establishment of hippocampal astrocyte polarity during postnatal maturation. This study thus reveals that Cx30 controls astroglial polarity during development.
5Altogether, these data highlight the important role of neuroglial interactions in brain physiological and pathological activities.
Publications
6Droguerre M., Tsurugizawa T., Duchêne A., Portal B., Guiard B.P., Déglon N., Rouach N., Hamon M., Mouthon F., Ciobanu L. et Charvériat M., « A new tool for in vivo study of astrocyte connexin 43 in brain », Scientific Reports, vol. 9, no 1, 2019, p. 18292, https://doi.org/10.1038/s41598-019-54858-9.
Walter A., van der Spek L., Hardy E., Bemelmans A., Rouach N. et Rancillac A., « Structural and functional connections between the median and the ventrolateral preoptic nucleus », Brain Structure and Function, vol. 224, no 9, 2019, p. 3045-3057.
Cresto N., Pillet L.E., Billuart P. et Rouach N., « Do astrocytes play a role in intellectual disabilities? », Trends in Neuroscience, vol. 42, no 8, 2019, p. 518-527.
Basnayake K., Mazaud D., Bemelmans A., Rouach N., Korkotian E. et Holcman D., « Fast calcium transients in neuronal spines driven by extreme statistics », PLoS Biology, vol. 17, no 6, 2019, e2006202.
Pannasch U., Dossi E., Ezan P. et Rouach N., « Astroglial Cx30 sustains neuronal population bursts independently of gap-junction mediated biochemical coupling », Glia, vol. 67, no 6, 2019, p. 1104-1112.
Blauwblomme T., Dossi E., Pellegrino C., Goubert E., Gal Iglesias B., Sainte-Rose C., Rouach N., Nabbout R. et Huberfeld G., « GABAergic transmission underlies interictal epileptogenicity in pediatric FCD », Annals of Neurology, vol. 85, no 2, 2019, 204-217.
Dallérac G., Zapata J. et Rouach N., « Versatile control of synaptic circuits by astrocytes: where, when and how? », Nature Reviews. Neuroscience, vol. 19, no 12, 2018, p. 729-743, https://doi.org/10.1038/s41583-018-0080-6.
Dossi E., Blauwblomme T., Moulard J., Chever O., Vasile F., Guinard E., Le Bert M., Couillin I., Pallud J., Capelle L., Hubergeld G. et Rouach N. « Pannexin 1 channels contribute to seizure generation in human epileptic brain tissue and in a mouse model of epilepsy », Science Translational Medicine, vol. 10, no 443, 2018, eaar3796, https://doi.org/10.1126/scitranslmed.aar3796.
Ghézali G., Calvo C.-F., Pillet L.-E., Llense F., Ezan P., Pannasch U., Etienne-Manneville S. et Rouach N., « Connexin 30 controls astroglial polarization during postnatal brain development », Development, vol. 145, no 4, 2018, dev155275, https://doi.org/10.1242/dev.155275.
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Référence papier
Nathalie Rouach, « Interactions neurogliales dans la physiologie et les pathologies cérébrales / Neuroglial interactions in cerebral physiology and pathologies », L’annuaire du Collège de France, 119 | 2022, 732-734.
Référence électronique
Nathalie Rouach, « Interactions neurogliales dans la physiologie et les pathologies cérébrales / Neuroglial interactions in cerebral physiology and pathologies », L’annuaire du Collège de France [En ligne], 119 | 2022, mis en ligne le 01 mars 2022, consulté le 16 février 2026. URL : http://journals.openedition.org/annuaire-cdf/17845 ; DOI : https://doi.org/10.4000/annuaire-cdf.17845
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