With Fat-1 mice, the present study tested the hypothesis that endogenously elevated brain n-3 PUFA concentrations can significantly attenuate LPS-induced depression-like behaviors through microglial activities, such as by inhibiting microglial M1 but enhancing the M2 phenotype, restoring astrocyte and neurotrophic function, and reducing proinflammatory cytokine production and apoptosis-related gene expression. The gene discussed is FAT1; the disease is major depressive disorder.