<scp>SARS</scp> ‐ <scp>C</scp> o <scp>V</scp> ‐2 Induces Prefrontal Hyperexcitability and Persistent Depressive Behaviors Rescued by Sertraline in h <scp>ACE</scp> 2 Transgenic Mice

ABSTRACT Post‐acute depressive disorders associated with COVID‐19 can persist for years after infection. However, the neurobiological mechanisms underlying their pathogenesis remain poorly understood. In this study, using a well‐established hACE2 transgenic mouse model, we observed persistent depression‐like behaviors. We detected direct SARS‐CoV‐2 infection in the olfactory bulb, which relayed acute inflammation to the prefrontal cortex (PFC), and indirectly, the systemic influence of SARS‐CoV‐2 infection on the brain, leading to long‐term dysregulation of serum corticosterone levels. While inflammatory or stress reactions caused no neuronal deficits in the acute phase, we found post‐acute synaptic plasticity impairment and increased apoptosis of PFC neurons, where severe mitochondrial injuries resulted from excessive aerobic respiration and reactive oxygen species (ROS) production. Our findings indicate that the PFC glutamatergic and GABAergic systems, which regulate brain excitatory and inhibitory balance, rather than monoaminergic systems, were most affected in post‐acute COVID‐19. Importantly, these behavioral abnormalities and neuronal damage were ameliorated with sertraline. Together, our findings support the hypothesis that post‐COVID depression involves sertraline‐reversible cortical hyperexcitability, providing a practical platform for mechanistic and translational research into post‐acute neuropsychiatric sequelae.