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

Abstract

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.

Mechanisms Underlying the Cognitive and Behavioural Effects of Maternal Obesity

“…Intriguing new evidence indicates that specific manipulations of nutrient content of the mother’s diet can alter microglial function. Madore et al [ 70 ] showed that offspring of mouse dams fed a diet deficient in n-3 fatty acids exhibited cognitive impairment (Y-maze and recognition memory tests) and disrupted microglial morphology in the CA1 region of hippocampus.…”

Strategies and Tools for Studying Microglial-Mediated Synapse Elimination and Refinement

“…PHrodo labeled SYNs were also used by Madore et al, to show the relevance of poly-unsaturated omega-3 fatty acids (n-3 PUFAs) in controlling microglial phagocytosis in the developing brain. In particular, exposing microglia deriving from either n-3 deficient or n-3 sufficient mice to pHrodo labeled SYN, the authors showed that the lack of n-3 from microglia increases the phagocytic capacity of microglial cells, inducing an excessive synaptic loss ( 148 ). Recently, Evans et al, exploited pHrodo labeled SYNs in order to show that beta-adrenergic antagonists, such as metropolol, are able to significantly increase phagocytosis of primary microglia from rats, whereas beta-adrenergic agonists, such as xamoterol and isoproterenol, attenuate SYNs engulfment ( 149 ).…”

Perinatal Dietary Polyunsaturated Fatty Acids in Brain Development, Role in Neurodevelopmental Disorders

“…Interestingly, recent data show that DHA in the membrane of glial cells regulates their activity, the formation of syncytium in astrocytes, neuroinflammation in microglia [ 7 ], or myelin formation in oligodendrocytes [ 58 ]. Of note, EPA is found in microglia [ 55 , 59 ], suggesting that these cells could play an important role in mediating the neuroprotective effect of EPA dietary supplementation in mood disorders [ 60 ]. However, the precise role of DHA, EPA, and ARA accretion in these cells during development and the impact of altered accretion on glial cell development remains to be investigated for both term and preterm neonates.…”