Brain exposure to SARS-CoV-2 virions perturbs synaptic homeostasis

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Partiot, Emma | Hirschler, Aurélie | Colomb, Sophie | Lutz, Willy | Claeys, Tine | Delalande, François | Deffieu, Maika, S | Bare, Yonis | Roels, Judith, Rebecca Elise | Gorda, Barbara | Bons, Joanna | Callon, Domitille | Andreoletti, Laurent | Labrousse, Marc | Jacobs, Frank, M J | Rigau, Valérie | Charlot, Benoit | Martens, Lennart | Carapito, Christine | Ganesh, Gowrishankar | Gaudin, Raphael

Edité par CCSD ; Nature Publishing Group -

International audience. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with short- and long-term neurological complications. The variety of symptoms makes it difficult to unravel molecular mechanisms underlying neurological sequalae after coronavirus disease 2019 (COVID-19). Here we show that SARS-CoV-2 triggers the up-regulation of synaptic components and perturbs local electrical field potential. Using cerebral organoids, organotypic culture of human brain explants from individuals without COVID-19 and post-mortem brain samples from individuals with COVID-19, we find that neural cells are permissive to SARS-CoV-2 to a low extent. SARS-CoV-2 induces aberrant presynaptic morphology and increases expression of the synaptic components Bassoon, latrophilin-3 (LPHN3) and fibronectin leucine-rich transmembrane protein-3 (FLRT3). Furthermore, we find that LPHN3-agonist treatment with Stachel partially restored organoid electrical activity and reverted SARS-CoV-2-induced aberrant presynaptic morphology. Finally, we observe accumulation of relatively static virions at LPHN3-FLRT3 synapses, suggesting that local hindrance can contribute to synaptic perturbations. Together, our study provides molecular insights into SARS-CoV-2-brain interactions, which may contribute to COVID-19-related neurological disorders.

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