SARS-CoV-2 spike protein S1 subunit induces neuroinflammation via microglial Kv1.3 channel

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. We performed the whole-cell patch clamp recording of microglia in CX 3 CR1 GFP/+ mice, Iba1 immunohistochemistry analysis and behavioral analysis. We found that the S1 protein increases 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. This study elucidates the molecular mechanism of S1 protein-mediated neuroinflammation and CPZ as a potential treatment for post-COVID symptoms.