Nat Microbiol


. 2024 Mar 28.
doi: 10.1038/s41564-024-01657-2. Online ahead of print. Brain exposure to SARS-CoV-2 virions perturbs synaptic homeostasis

Emma Partiot 1 2 , Aurélie Hirschler 3 4 , Sophie Colomb 5 6 , Willy Lutz 1 2 7 , Tine Claeys 8 9 , François Delalande 3 4 , Maika S Deffieu 1 2 , Yonis Bare 1 2 , Judith R E Roels 10 , Barbara Gorda 1 2 , Joanna Bons 3 4 , Domitille Callon 11 12 , Laurent Andreoletti 11 12 , Marc Labrousse 12 13 , Frank M J Jacobs 10 , Valérie Rigau 2 14 , Benoit Charlot 2 15 , Lennart Martens 8 9 , Christine Carapito 3 4 , Gowrishankar Ganesh 2 7 , Raphael Gaudin 16 17



AffiliationsAbstract

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.