Simulated microgravity affects neuronal synaptic plasticity by regulating microglial pro-inflammatory activation

As resident immune cells of the central nervous system, microglia exhibit inherent responsiveness to external stimuli and insults. In this study, we demonstrated that a simulated microgravity conditions induces pro-inflammatory activation of BV2 microglial cells, a process tightly regulated by the RhoA GTPase Arhgap18. Specifically, the downregulation of Arhgap18 under simulated microgravity was identified as the upstream mechanism driving microglial activation and triggering neuroinflammation via the Arhgap18/RhoA/ROCK signaling pathway. For in vivo validation, we established a 21-day hindlimb unloading (HU) mouse model, which confirmed that simulated microgravity promotes pro-inflammatory microglial activation in the cerebral cortex and hippocampus. Furthermore, co-culture of N2a neural cells with pro-inflammatory microglia led to distinct morphological alterations in N2a cells and a significant downregulation of synaptic plasticity-related proteins—effects that were recapitulated in the HU mouse model. Collectively, these findings suggest that microgravity may mediate changes in neuronal synaptic plasticity by activating the inflammatory response of microglia.