Exposure to SARS-CoV-2 Spike protein during development induces astrogliosis, synapse loss and long-term cognitive dysfunction in mice.

Exposure to pathogens can be extremely harmful to the developing brain. Even though the Coronavirus Disease-19 (COVID-19) pandemic has subsided, the actual impact of exposure to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during neurodevelopment remains poorly understood. Although vertical transmission of SARS-CoV-2 is rare, the viral Spike protein has been detected in the placenta and fetus even without detectable viral RNA. Here, we investigated whether exposure to SARS-CoV-2 Spike protein during neurodevelopment compromises brain function and behavior. We found that a single neonatal injection of the Spike protein in mice increases seizure susceptibility, induces astrogliosis, and triggers a significant loss of excitatory and inhibitory synapses in the cortex and hippocampus within 10 days. Remarkably, 60 days post-Spike protein exposure, male mice exhibited persistent, sex-specific cognitive impairments. This behavioral phenotype correlated with a chronic, sex-specific neuroinflammatory footprint, suggesting that a failure to resolve glial reactivity may drive the long-term deficits observed specifically in Spike-injected male mice. Cognitive deficits were replicated using a live SARS-CoV-2 infection model in wild-type mice, confirming that cognitive disruption occurs independently of robust viral replication. Our findings underscore the vulnerability of the developing brain to viral components and highlight the need to monitor long-term outcomes following perinatal COVID-19 exposure.