Transgenic increase in n-3/n-6 fatty acid ratio protects against cognitive deficits induced by an immune challenge through decrease of neuroinflammation

Neuropsychopharmacology. 2015 Feb;40(3):525-36. doi: 10.1038/npp.2014.196. Epub 2014 Aug 5.


Polyunsaturated fatty acids (PUFAs) display immunomodulatory properties in the brain, n-3 PUFAs being able to reduce inflammation whereas n-6 PUFAs are more pro-inflammatory. It has been extensively demonstrated that exposure to a peripheral immune challenge leads to the production and release of inflammatory mediators in the brain in association with cognitive deficits. The question arises whether n-3 PUFA supplementation could downregulate the brain inflammatory response and subsequent cognitive alterations. In this study, we used a genetically modified mouse line carrying the fat-1 gene from the roundworm Caenorhabditis elegans, encoding an n-3 PUFA desaturase that catalyzes conversion of n-6 into n-3 PUFA. Consequently, these mice display endogenously elevated n-3 PUFA tissue contents. Fat-1 mice or wild-type (WT) littermates were injected peripherally with lipopolysaccharide (LPS), a bacterial endotoxin, to induce an inflammatory episode. Our results showed that LPS altered differently the phenotype of microglia and the expression of cytokines and chemokines in Fat-1 and WT mice. In Fat-1 mice, pro-inflammatory factors synthesis was lowered compared with WT mice, whereas anti-inflammatory mechanisms were favored 24 h after LPS treatment. Moreover, LPS injection impaired spatial memory in WT mice, whereas interestingly, the Fat-1 mice showed normal cognitive performances. All together, these data suggest that the central n-3 PUFA increase observed in Fat-1 mice modulated the brain innate immune system activity, leading to the protection of animals against LPS-induced pro-inflammatory cytokine production and subsequent spatial memory alteration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Cytokines / metabolism
  • Fatty Acid Desaturases / genetics
  • Fatty Acids, Omega-3 / metabolism*
  • Fatty Acids, Omega-6 / metabolism*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Illness Behavior / drug effects
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / pharmacology
  • Male
  • Maze Learning / drug effects
  • Memory Disorders / chemically induced
  • Memory Disorders / genetics
  • Memory Disorders / prevention & control*
  • Mice
  • Mice, Transgenic
  • Microglia / immunology
  • Phenotype
  • Spatial Memory / drug effects


  • Caenorhabditis elegans Proteins
  • Cytokines
  • Fatty Acids, Omega-3
  • Fatty Acids, Omega-6
  • Inflammation Mediators
  • Lipopolysaccharides
  • fat-1 protein, C elegans
  • Fatty Acid Desaturases