Dietary polyunsaturated fatty acids tune neurodevelopment through microglia-neuron interactions
Polyunsaturated fatty acids (PUFAs) are essential fatty acids belonging to 2 distinct families n-3 (or omega 3) and n-6 (or omega6). As our organism cannot produce them, they have to be provided through the diet. Once digested, PUFAs reach organs through the blood circulation and incorporate into cell membrane or are metabolized into other lipid signaling molecules. The brain is one of the richest organs in PUFAs. In humans, poor levels of blood and brain n-3 PUFAs are associated to a higher prevalence of psychiatric disorders, including neurodevelopmental disorders. However, the mechanisms underlying the effect of n-3 PUFA deficiency on brain functions are still poorly understood.
To study the impact of n-3 PUFA deficiency on brain development, we used a mice model of nutritional n-3 PUFA deficiency from the first day of gestation until weaning. At weaning, working memory and neuronal structure and functioning were assessed in the hippocampus using a combination of molecular, imaging and behavioral approaches. Then microglia profile and phagocytic activity were assessed using FACS, RNAseq and lipidomic approaches. To further link phagocytic activity, complement system, PUFA derivatives and behavior, in vitro and in vivo pharmacological approaches were used.
Using a mice model of early-life n-3 PUFAs dietary deficiency, we revealed that the development of the hippocampus is altered, leading to altered neuronal morphology and affecting cognitive performance. We further revealed that dietary n-3 PUFA deficiency increases microglia (the main innate immune system cell in the brain)-mediated phagocytosis of synaptic elements. In addition, we revealed that microglia specific molecular pathways involving the complement system and 12/15-lipoxygenase (LOX)/12-HETE signaling are responsible of altered synaptic pruning. Altogether, our work brings a better comprehension of how early-life dietary n-3 PUFAs contribute to brain development and risk of disorders such as neurodevelopmental disorders.