Postnatal immune activation (PIA) can affect normal brain development and increase the risk of behavioral abnormalities in later life, including depressive-like behavior. Therefore, there is an urgent need to find safe and effective clinical medications for PIA. Recently, the protective effect of
astilbin (ASB) in
nervous system diseases has attracted much attention. However, the effect of ASB on neurodevelopmental diseases remains unclear. In this study, we used a
lipopolysaccharide (LPS)-induced PIA mouse model and found that ASB specifically improved PIA-induced depressive-like behavior but not anxiety-like behavior in adult mice. Astrocytes play an essential role in regulating
neuroinflammation, and are the most abundant cell type in the brain. In the PIA model, we found that ASB selectively inhibited astrocyte activation but not microglial activation in the cortex and hippocampus. Moreover, our results showed that ASB specifically upregulated the expression of menin
protein in astrocytes and blocked the entry of P65
protein into the nucleus, thus inhibiting the secretion of IL-1β and TNF-α by astrocytes. Taken together, ASB reduced the occurrence of astrocyte-mediated
neuroinflammation by targeting menin, thereby attenuating the PIA-induced depressive-like behavior. Our results reveal that ASB may be an attractive
antidepressant drug and exert an
antidepressant effect in PIA. In terms of
drug selection, ASB may be a specific
drug for patients with depressive symptoms.