Omega-3 fatty acids (n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in Humans. However, the n-3 PUFAs deficiency-mediated mechanisms affecting the development of the central nervous system are poorly understood. Active microglial engulfment of synapses regulates brain development. Impaired synaptic pruning is associated with several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development in mice. Our results show that maternal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the rodent developing hippocampus, partly through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, altering neuronal morphology and affecting cognitive performance of the offspring. These findings provide a mechanistic insight into neurodevelopmental defects caused by maternal n-3 PUFAs dietary deficiency.

Author's contributions CB designed, performed and analyzed most of the experiments. EM performed transcriptomic meta-analyses, behavioral and molecular studies. EP, MDM, MM, SP, SLa, XF, LV performed and analyzed ex vivo patch-clamp electrophysiology. DS, YN, MB, XSD performed human studies and data analysis. ST, FM and PF performed and analyzed in vivo electrophysiology recordings. MAS performed the RNAscope and lipidomics studies. JC helped with surgery and behavioral procedures. CMo helped performing western blots and dissections. CMa designed and performed doppler imaging and fiber photometry experiments. MCad and SC designed and performed self-administration experiments. JHS and CBJ performed the iDISCO analysis. MHT, GG, TSH and SL secured funding. TSH and DS provided scientific guidance and experimental design. SL and GG supervised the whole project, interpreted the data and wrote the manuscript with contribution from all coauthors.