SARS-CoV-2 Spike Protein S1 Subunit Induces Neuroinflammation Via Microglial Kv1.3 Channel

Background: Neuroinflammation is a hallmark of various neurological and psychiatric disorders, including post-COVID-19 conditions caused by SARS-CoV-2 infection. The S1 subunit of the SARS-CoV-2 spike protein (S1 protein) can trigger neuroinflammation by activating microglia. However, the precise mechanism of S1 protein-induced microglial activation remains unclear. Our investigation revealed that the Kv1.3 channel plays a role in S1 protein-mediated neuroinflammation. Methods: mice, Iba1 immunohistochemistry analysis, and behavioral analysis. Results: We found that the S1 protein increased Kv1.3 channel activity and microglial activation in the lateral septum, leading to behavioral changes. Chlorpromazine (CPZ), an antipsychotic linked to lower COVID-19 rates in clinical observations, blocked S1 protein-mediated increase in Kv1.3 channel current and microglia size. Mice injected with the S1 protein showed anxiety-like behavior, which CPZ alleviated. Conclusions: This study elucidates the molecular mechanism of S1 protein-mediated neuroinflammation and CPZ as a potential treatment for post-COVID symptoms.