Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Madore, C.; Leyrolle, Q.; Morel, L.; Delpech, J.-C.; Greenhalgh, A. D.; Lacabanne, C.; Bosch-Bouju, C.; Bourel, J.; Thomazeau, A.; Hopperton, K. E.; Beccari, S.; Sere, A.; Aubert, A.; De Smedt-Peyrusse, V.; Lecours, C.; Bisht, K.; Fourgeaud, L.; Gregoire, S.; Bretillon, L.; Grant, N. J.; Badaut, J.; Gressens, P.; Sierra, A.; Butovsky, O.; Tremblay, M.-E.; Bazinet, R. P.; Joffre, C.; Nadjar, A.; Laye, S.

doi:10.1101/744136

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bioRxiv · 10.1101/744136

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

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Abstract

Omega-3 fatty acids (n-3 polyunsaturated 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 epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, through the activation of 12/15- lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.\n\nOne Sentence SummaryLow maternal omega-3 fatty acids intake impairs microglia-mediated synaptic refinement via 12-HETE pathway in the developing brain.

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Madore, C., Leyrolle, Q., Morel, L., Delpech, J.-C., Greenhalgh, A. D., Lacabanne, C., Bosch-Bouju, C., Bourel, J., Thomazeau, A., Hopperton, K. E., Beccari, S., Sere, A., Aubert, A., De Smedt-Peyrusse, V., Lecours, C., Bisht, K., Fourgeaud, L., Gregoire, S., Bretillon, L., Grant, N. J., Badaut, J., Gressens, P., Sierra, A., Butovsky, O., Tremblay, M.-E., Bazinet, R. P., Joffre, C., Nadjar, A., Laye, S.. 2019-09-04. Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain. https://doi.org/10.1101/744136

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