Journal
MOLECULAR PSYCHIATRY
Volume 27, Issue 10, Pages 3939-3950Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-022-01786-2
Keywords
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Funding
- Hjarnfonden postdoktorala stipendier [PS2019-0040, PS2018-0058]
- Swedish Society for Medical Research [P18-0120]
- Swedish Research Council [2017-02559]
- Karolinska Institutet
- Stockholm County Council
- Marianne and Marcus Wallenberg Foundation
- One Mind Foundation/Kaiser Permanente
- Swedish Research Council [2017-02559] Funding Source: Swedish Research Council
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Neuropsychiatric manifestations are common in SARS-CoV-2 infection, but their mechanisms are unknown. Using a brain organoid model, researchers found that SARS-CoV-2 infection triggers neuronal cell death and disrupts circuit integrity through microglia-mediated synapse elimination, potentially contributing to cognitive impairments in COVID-19 patients.
Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection initiate neuronal cell death and cause a loss of post-synaptic termini. Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure. We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synapse engulfment. To a large extent, SARS-CoV-2 exposed microglia adopt a transcriptomic profile overlapping with neurodegenerative disorders that display an early synapse loss as well as an increased incident risk after a SARS-CoV-2 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from COVID-19.
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