Dietary n-3 PUFAs Deficiency Increases Vulnerability to Inflammation-Induced Spatial Memory Impairment

Abstract

Dietary n-3 polyunsaturated fatty acids (PUFAs) are critical components of inflammatory response and memory impairment. However, the mechanisms underlying the sensitizing effects of low n-3 PUFAs in the brain for the development of memory impairment following inflammation are still poorly understood. In this study, we examined how a 2-month n-3 PUFAs deficiency from pre-puberty to adulthood could increase vulnerability to the effect of inflammatory event on spatial memory in mice. Mice were given diets balanced or deficient in n-3 PUFAs for a 2-month period starting at post-natal day 21, followed by a peripheral administration of lipopolysaccharide (LPS), a bacterial endotoxin, at adulthood. We first showed that spatial memory performance was altered after LPS challenge only in n-3 PUFA-deficient mice that displayed lower n-3/n-6 PUFA ratio in the hippocampus. Importantly, long-term depression (LTD), but not long-term potentiation (LTP) was impaired in the hippocampus of LPS-treated n-3 PUFA-deficient mice. Proinflammatory cytokine levels were increased in the plasma of both n-3 PUFA-deficient and n-3 PUFA-balanced mice. However, only n-3 PUFA-balanced mice showed an increase in cytokine expression in the hippocampus in response to LPS. In addition, n-3 PUFA-deficient mice displayed higher glucocorticoid levels in response to LPS as compared with n-3 PUFA-balanced mice. These results indicate a role for n-3 PUFA imbalance in the sensitization of the hippocampal synaptic plasticity to inflammatory stimuli, which is likely to contribute to spatial memory impairment.

Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

“…As a consequence, a diet rich in DHA in humans is associated with a decreased risk of developing neurological disorders with an inflammatory component, such as Alzheimer's disease or depression [41][42][43]. In animal models, our laboratory demonstrated that neuroinflammatory processes are over-activated in the brain of mice fed a diet deficient for ω-3 PUFAs [26,44]. Conversely, ω-3 PUFA brain enrichment protects against deleterious effects of inflammation on cognitive performances [24,45,46] …”

Neuroinflammatory processes in cognitive disorders: Is there a role for flavonoids and n-3 polyunsaturated fatty acids in counteracting their detrimental effects?

“…In vivo, chronic dietary LC n-3 PUFA deficiency significantly affected microglia activity and increased the release of IL-6 and TNF-α in the blood of rat (McNamara et al, 2010) and in the hippocampus of mice at post-natal day 21 (Madore et al, 2014), which was not observed in the brain of adult and aged mice (Delpech et al, 2015c;Mingam et al, 2008;Moranis et al, 2012). Alternatively, both in vivo and in vitro studies have reported anti-inflammatory activities of LC n-3 PUFA in the brain especially in microglia (Laye, 2010;Orr and Bazinet, 2008) and currently supports: 1) a capacity to down-regulate the activity of proinflammatory transcription factors such as NF-κB, 2) an inhibitory role on the release of cytokines, such as interleukin IL-1β and TNF-α, from activated microglia, 3) an inhibitory action against the production of NO and PGE2 in response to microglia activation, 4) a beneficial action on membrane lipid composition, lipid rafts and membrane receptors incorporation such as TLR receptors, and 5) a capacity to elicit peripheral and central proresolutive processes by activating phagocytosis and promoting polarization of glial cells toward a M2-like phenotype.…”

“…Another important mediator of anti-inflammatory activity of DHA is neuroprotectin D1 (NPD1) (Bazan, 2006;Bazan et al, 2012). Infusion of DHA and NPD1 in the brain was reported to be acutely protective toward brain cytokine production and microglia activation (Lukiw et al, 2005;Orr et al, 2013) protecting brain from bacterial endotoxin-induced synaptic plasticity impairment and ageing (Delpech et al, 2015a;Delpech et al, 2015c;Labrousse et al, 2012). NPD1 was also shown to inhibit leukocyte infiltration, COX-2 expression, and NFκB activation in vivo and in vitro (Marcheselli et al, 2010).…”

Role of n-3 PUFAs in inflammationviaresolvin biosynthesis

“…These changes in n-3 PUFAs in the diet lead to modifications in the n-3 PUFA content in the brain. As a result, we have previously demonstrated that low dietary intake of n-3 PUFAs promotes neuroinflammatory responses through the regulation of microglial cell activity and polarization toward a pro-inflammatory phenotype, whereas n-3 PUFA dietary supplementation is rather anti-inflammatory (Delpech et al, 2015c;De Smedt-Peyrusse et al, 2008;Labrousse et al, 2012;Madore et al, 2014;Mingam et al, 2008). Moreover, the central n-3 PUFA increase observed in transgenic Fat-1 mice modulates the brain innate immune system activity, leading to the protection of animals against LPS-induced pro-inflammatory cytokine production and subsequent spatial memory alteration (Delpech et al, 2015a).…”