Activation of microglial G‑protein-coupled receptor 30 protects neurons against excitotoxicity through NF-κB/MAPK pathways

•Microglial GPR30 was involved in the neuroexcitotoxicity.•Glutamate caused the activation and inflammatory response in microglia.•Microglial GPR30 played the neuroprotective role through NF-κB/MAPK pathways.•Microglial GPR30 protected neurons from neuroexcitotoxicity. Neuroexcitotoxicity is a common feature in neuronal damage and neurodegenerative diseases. Our previous studies have confirmed that neuronal and astrocytic G‑protein-coupled receptor 30 (GPR30) play a key role in neuroprotection in vivo and in vitro. Microglia are considered as immune cells in the central nervous system. However, the role of microglial GPR30 in neuroprotection against neuroexcitotoxicity remained unclear. In this study, MTT, Western blot, immunocytochemical staining, phagocytosis assay and wound healing assay were employed to detect the effect of GPR30 in N9 microglial cells after exposure to glutamate. We found that the treatment of GPR30 specific agonist G1 inhibited glutamate-induced proliferation and activation in N9 microglial cells. G1 inhibited M1 polarization, facilitated M2 polarization, and decreased over-phagocytosis but had no effect on migration ability in microglia. The result of neurons and microglia co-culture showed that the activation of microglial GPR30 protected neurons from excitotoxicity through the NF-κB/MAPK signaling pathways. Our findings suggested a key role of microglial GPR30 in excitatory neuronal damage and neurodegenerative diseases.