Microglia is the main cellular component of the cerebral innate immune system. During a peripheral immune challenge, microglial cells are activated, leading to alteration of hippocampal memory. This modulation of cognitive processes is exerted by signals produced by immune-like processes and in particular the proinflammatory cytokine Interleukin-1 beta (IL-1β). Depending on the type of signals produced after an inflammatory event, microglia develops specific activities, including cytotoxic, neuroprotective or phagocytic activities in order to come back to brain homeostasis. As described for macrophages, microglia can adopt M1 (proinflammatory) or M2 (phagocytic) phenotypes distinguishable through their pattern of factors expression and specific cell surface markers. Interestingly, polyunsaturated fatty acids (PUFAs) are precursors of bioactive lipid messengers involved in the regulation of inflammation and in particular, docosahexanoic acid (DHA, 22:6n-3) an n-3 PUFA, presents anti-inflammatory properties. The aim of our study was thus to investigate the effect of an increase of n-3 PUFAs on the inflammatory response and cognitive abilities after a peripheral immune challenge. To increase n-3 PUFAs, we took advantage of transgenic mice carrying the fat-1 gene from the roundworm Caenorhabditis elegans. This fat-1 transgenic mouse is capable of producing n-3 fatty acids from the n-6 type endogenously, eliminating confounding factors of the diet. This conversion leads to abundant n-3 fatty acids with reduced levels of n-6 fatty acids in tissues, including the brain. To induce a neuroinflammation, we injected mice intraperitoneally with lipopolysaccharide (LPS), components of gram negative bacteria walls. We first studied the microglial phenotype 24 h after LPS injection and found that microglia in Fat-1 mice presented a significant increase of M2 phenotype markers. We then measured cytokine expression in the hippocampus after a LPS challenge and found a significant decrease in IL-1β mRNA in Fat-1mice compared to wild-type littermates. In terms of hippocampal memories abilities, only control mice presented a deficit in the Y-maze task whereas Fat-1 mice were able to perform the test correctly. Our results indicate that 24 h after a LPS injection, Fat-1 mice presented a decreased of the inflammatory response and normal hippocampal memory abilities compared to wild-type littermates.