N‐3 PUFA deficiency disrupts oligodendrocyte maturation and myelin integrity during brain development

Abstract

Westernization of dietary habits has led to a progressive reduction in dietary intake of n‐3 polyunsaturated fatty acids (n‐3 PUFAs). Low maternal intake of n‐3 PUFAs has been linked to neurodevelopmental disorders, conditions in which myelination processes are abnormal, leading to defects in brain functional connectivity. Only little is known about the role of n‐3 PUFAs in oligodendrocyte physiology and white matter development. Here, we show that lifelong n‐3 PUFA deficiency disrupts oligodendrocytes maturation and myelination processes during the postnatal period in mice. This has long‐term deleterious consequences on white matter organization and hippocampus‐prefrontal functional connectivity in adults, associated with cognitive and emotional disorders. Promoting developmental myelination with clemastine, a first‐generation histamine antagonist and enhancer of oligodendrocyte precursor cell differentiation, rescues memory deficits in n‐3 PUFA deficient animals. Our findings identify a novel mechanism through which n‐3 PUFA deficiency alters brain functions by disrupting oligodendrocyte maturation and brain myelination during the neurodevelopmental period.

N-3 PUFA Deficiency Affects the Ultrastructural Organization and Density of White Matter Microglia in the Developing Brain of Male Mice

“…We chose the latter based on the previous studies on myelin/microglia interactions during development (Hagemeyer et al, 2017;Kaur et al, 2017;Lee et al, 2019;Nemes-Baran et al, 2020;Traiffort et al, 2020). This is also in this area that we observed an alteration of myelination in mice deficient in n-3 PUFA in a former study (Leyrolle et al, 2021b). We focused on one part of the corpus callosum, the body that unites the motor, somatosensory and parietal regions (Wahl et al, 2007;Park et al, 2008;Putnam et al, 2010;Ku and Torii, 2020).…”

“…In line with this assumption, Kalafatakis and Karagogeos, 2021 have shown that the time course of microglial migration to the white matter correlates with the onset of OPCs generation in this structure. Interestingly, we previously demonstrated that maternal n-3 PUFA deficiency leads to hypomyelination of the corpus callosum at P21 and in the adult offspring, and to a significant decrease in the number of mature oligodendrocytes in the corpus callosum of juveniles, associated with long-term deficits in brain structures synchronization ( Leyrolle et al, 2021b ). Hence, while the total number of microglia was similar between both dietary groups at P15, the absence of a peak at P10 in n-3 deficient mice may have significant functional impacts.…”

“…Litter size at birth is around 12 pups per dam. CD1 juvenile (P0, P5, P10, P15) males were used for the experiments as our previous results, where we observed myelination alterations, were also obtained in male mice ( Leyrolle et al, 2021b ). Moreover, the literature on microglia/myelin interactions focuses on males ( Hagemeyer et al, 2017 ; Hughes and Appel, 2019 ; Li et al, 2019 ).…”

“…During gestation and lactation, CD1 dams (obtained from Janvier Labs at 2 months of age) were fed with isocaloric diets (from INRAE Jouy en Josas) containing 5% fat with low (n-3 PUFA sufficient group) or high (n-3 PUFA deficient group) n-6/n-3 precursor ratio, respectively, α-linolenic acid (ALA, 18:3 n-3) and linoleic acid (LA, 18:2 n-6) (detailed composition is reported in Tables 1 , 2 ), according to the international nutritional recommendations and as previously published ( Delpech et al, 2015 ; Labrousse et al, 2018 ; Decoeur et al, 2020 ; Madore et al, 2020 ; Leyrolle et al, 2021a , b ). We could not observe any effect of the diet on maternal behavior (e.g., active nursing, pups licking/sniffing, nesting) or litter size (unpublished observations.…”

“…We could not observe any effect of the diet on maternal behavior (e.g., active nursing, pups licking/sniffing, nesting) or litter size (unpublished observations. We previously reported that decreasing the amount of n-3 PUFA precursors in the maternal diet led to a significant increase in the n-6 PUFA/n-3 PUFA ratio in the pups’ brain structures, white matter and microglial cells ( Joffre et al, 2016 ; Madore et al, 2020 ; Leyrolle et al, 2021b ).…”