Short-Term Long Chain Omega3 Diet Protects from Neuroinflammatory Processes and Memory Impairment in Aged Mice

Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs) has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this purpose, mice were exposed to a control diet throughout life and were further submitted to a diet enriched in EPA and DHA during 2 additional months. Cytokine expression together with a thorough analysis of astrocytes morphology assessed by a 3D reconstruction was measured in the hippocampus of young (3-month-old) and aged (22-month-old) mice. In addition, the effects of EPA and DHA on spatial memory and associated Fos activation in the hippocampus were assessed. We showed that a 2-month EPA/DHA treatment increased these long-chain ω3 PUFAs in the brain, prevented cytokines expression and astrocytes morphology changes in the hippocampus and restored spatial memory deficits and Fos-associated activation in the hippocampus of aged mice. Collectively, these data indicated that diet-induced accumulation of EPA and DHA in the brain protects against neuroinflammation and cognitive impairment linked to aging, further reinforcing the idea that increased EPA and DHA intake may provide protection to the brain of aged subjects

Impaired Interleukin-1β and c-Fos Expression in the Hippocampus Is Associated with a Spatial Memory Deficit in P2X7 Receptor-Deficient Mice

Recent evidence suggests that interleukin-1β (IL-1β), which was originally identified as a proinflammatory cytokine, is also required in the brain for memory processes. We have previously shown that IL-1β synthesis in the hippocampus is dependent on P2X7 receptor (P2X7R), which is an ionotropic receptor of ATP. To substantiate the role of P2X7R in both brain IL-1β expression and memory processes, we examined the induction of IL-1β mRNA expression in the hippocampus of wild-type (WT) and homozygous P2X7 receptor knockout mice (P2X7R−/−) following a spatial memory task. The spatial recognition task induced both IL-1β mRNA expression and c-Fos protein activation in the hippocampus of WT but not of P2X7R−/− mice. Remarkably, P2X7R−/− mice displayed spatial memory impairment in a hippocampal-dependant task, while their performances in an object recognition task were unaltered. Taken together, our results show that P2X7R plays a critical role in spatial memory processes and the associated hippocampal IL-1β mRNA synthesis and c-Fos activation

Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice

Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-Aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with a reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-Activated long-Term depression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic and behavioral phenomena were reversed by knocking down Homer1a in Fmr1 KO mice. Our study provides a mechanistic link between changes of mGluR5 dynamics and pathological phenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics

Dietary prevention of visual function and cognitive decline by omega-3 polyunsaturated fatty acids in Senescence Accelerated Mouse P8 (SAM P8)

International audiencePurpose: : Neuronal tissues such as the brain and the retina contain elevated amounts of long-chain omega-3 polyunsaturated fatty acids (PUFAs) and particularly docosahexaenoic acid (DHA). DHA concentrations are known to decrease in the aging brain and are associated with cognitive decline. The senescence-accelerated mouse prone 8 (SAM P8) is a mouse model for aging that exhibits deficits in cognitive performances as well as alterations of retinal functionality (ARVO 2004 E-abstract 797). The aim of this study was to evaluate the effects of a dietary supplementation with DHA on mood, cognition and visual functionality of SAM P8 during aging. Methods: : SAM P8 mice were studied in comparison with SAM resistant 1 control animals (SAM R1). Animals were fed from weaning until 12 months of age with either a control diet balanced in omega-3 and omega-6 PUFAs but without DHA, a diet deficient in omega-3 PUFAs or a diet containing 6% of lipids as DHA. After 5 and 12 months of diet, the scotopic ERG was recorded and working memory and despair behavior were evaluated. The fatty acid composition of the retina and the brain was determined using capillary column gas chromatography. Results: : Dietary supplementation with long-chain omega-3 PUFAs led to significantly higher retinal and cerebral levels of DHA. The incorporation rate was significantly higher in SAM P8 when compared to SAM R1. An age-related diminution of the ERG b-wave amplitude was observed from 5 to 12 months of age in control and deficient SAM P8 when compared to SAM R1. These differences were emphasized in deficient animals. No age-related alteration of the ERG b-wave amplitude was observed in SAM P8 Meanwhile dietary supplementation with DHA reduced the duration of immobility in the forced swimming test in SAM R1 but not in SAM P8. Conclusions: : Dietary supplementation with DHA was efficient in increasing its retinal and cerebral incorporation. DHA successfully prevented the age-related loss of visual function in SAM P8 but did not improve the depression-like symptoms

Hippocampal Mossy Fibers Synapses in CA3 Pyramidal Cells Are Altered at an Early Stage in a Mouse Model of Alzheimer's Disease

International audienceEarly Alzheimer's disease (AD) affects the brain non-uniformly, causing hippocampal memory deficits long before widespread brain degeneration becomes evident. Here we addressed whether mossy fiber inputs from the dentate gyrus onto CA3 principal cells are affected in an AD mouse model before amyloid ␤ plaque deposition. We recorded from CA3 pyramidal cells in a slice preparation from 6-month-old male APP/PS1 mice, and studied synaptic properties and intrinsic excitability. In parallel we performed a morphometric analysis of mossy fiber synapses following viral based labeling and 3D-reconstruction. We found that the basal structural and functional properties as well as presynaptic short-term plasticity at mossy fiber synapses are unaltered at 6 months in APP/PS1 mice. However, transient potentiation of synaptic transmission mediated by activity-dependent release of lipids was abolished. Whereas the presynaptic form of mossy fiber long-term potentiation (LTP) was not affected, the postsynaptic LTP of NMDAR-EPSCs was reduced. In addition, we also report an impairment in feedforward inhibition in CA3 pyramidal cells. This study, together with our previous work describing deficits at CA3-CA3 synapses, provides evidence that early AD affects synapses in a projection-dependent manner at the level of a single neuronal population

Preference for novelty was measured using a 2-min ITI in WT and P2X7R^−/− mice.

<p>Both strain exhibited a clear preferential exploration of the novelty (Arm effect, ***p<0.001).</p

IL-1β mRNA expression after the exposure to the Y maze in P2X₇R^−/− mice.

<p>IL-1β mRNA was measured by real-time PCR on WT and P2X₇R^−/− mice sacrificed either after free exploration (control group) or completion of behavioral testing (Y-maze group). All data are expressed as mean relative fold change±SEM (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006006#s2" target="_blank">Materials and Methods</a> for explanation). (A) IL-1β mRNA on hippocampus extracts from the 2-min ITI Y-maze group and their controls (left-hand panel) and the 30-min ITI Y-maze group and their controls (right-hand panel). (B) IL-1β mRNA on hypothalamus extracts from the 30-min ITI Y-maze group and their controls. Y maze exposure significantly increased the IL-1β mRNA expression in the hippocampus of WT mice but not of P2X₇R^−/− mice. Whatever the group considered (WT or P2X₇R^−/−), no induction of IL-1β mRNA expression was detected in hypothalamus after the Y maze experience. ***p<0.001, **p<0.01.</p

Recognition memory performance after 30 minutes of retention in P2X₇R^−/− mice.

<p>(A) Time spent (sec) in the novel or the familiar arm after a 30-min ITI. (B) Time spent (sec) exploring the novel or the familiar object after a 30-min ITI. Spatial recognition memory, but not object recognition memory, was impaired in P2X₇R^−/− mice after a 30-min ITI. ***p<0.001, **p<0.01,*p<0.05.</p

Dietary omega-3 deficiency exacerbates inflammation and reveals spatial memory deficits in mice exposed to lipopolysaccharide during gestation.

International audienceMaternal immune activation (MIA) is a common environmental insult on the developing brain and represents a risk factor for neurodevelopmental disorders. Animal models of in utero inflammation further revealed a causal link between maternal inflammatory activation during pregnancy and behavioural impairment relevant to neurodevelopmental disorders in the offspring. Accumulating evidence point out that proinflammatory cytokines produced both in the maternal and fetal compartments are responsible for social, cognitive and emotional behavioral deficits in the offspring. Polyunsaturated fatty acids (PUFAs) are essential fatty acids with potent immunomodulatory activities. PUFAs and their bioactive derivatives can promote or inhibit many aspects of the immune and inflammatory response. PUFAs of the n-3 series ('n-3 PUFAs', also known as omega-3) exhibit anti-inflammatory/pro-resolution properties and promote immune functions, while PUFAs of the n-6 series ('n-6 PUFAs' or omega-6) favor pro-inflammatory responses. The present study aimed at providing insight into the effects of n-3 PUFAs on the consequences of MIA on brain development. We hypothesized that a reduction in n-3 PUFAs exacerbates both maternal and fetal inflammatory responses to MIA and later-life defects in memory in the offspring. Based on a lipopolysaccharide (LPS) model of MIA (LPS injection at embryonic day 17), we showed that n-3 PUFA deficiency 1) alters fatty acid composition of the fetal and adult offspring brain; 2) exacerbates maternal and fetal inflammatory processes with no significant alteration of microglia phenotype, and 3) induces spatial memory deficits in the adult offspring. We also showed a strong negative correlation between brain content in n-3 PUFA and cytokine production in MIA-exposed fetuses. Overall, our study is the first to address the deleterious effects of n-3 PUFA deficiency on brain lipid composition, inflammation and memory performances in MIA-exposed animals and indicates that it should be considered as a potent environmental risk factor for the apparition of neurodevelopmental disorders

Brain fatty acid composition.

<p>dGLA: dihomo-gamma-linolenic acid (20:3 ω6); AA: arachidonic acid (20:4 ω6); EPA: eicosapentaenoic acid (20:5 ω3); DHA: docosahexaenoic acid; DMA: dimethyl acetal; LC ω6: long chain ω6 (20:2 ω6+20:3 ω6+20:4 ω6+22:4 ω6+22:5 ω6); LC ω3: long chain ω3 (20:5 ω3+22:5 ω3+22:6 ω3); NS: not significant.</p>***<p>p<0.001 as compared to aged control diet;</p>**<p>p<0.01 as compared to aged control diet;</p>*<p>p<0.05 as compared to aged control diet.</p