Chronic dietary changes in n-6/n-3 polyunsaturated fatty acid ratios cause developmental delay and reduce social interest in mice

Elst, Kim van; Brouwers, Jos F.; Merkens, Jessica E.; Broekhoven, Mark H.; Birtoli, Barbara; Helms, J. Bernd; Kas, Martien

doi:10.1016/j.euroneuro.2018.11.1106

Cited by 15 publications

(12 citation statements)

References 72 publications

(106 reference statements)

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“…Noteworthily, a recent publication demonstrated social deficits when shifting the dietary fatty acid composition, specifically the ratio between ω-3- and ω-6-containing fatty acids, in mice [54]. We have shown previously that, in the murine brain, ether lipid deficiency is mainly compensated by increased levels of ω-6-containing phosphatidylethanolamine species, thus shifting the ω-3/ ω-6 balance in the abundant group of ethanolamine phospholipids [55].…”

Section: Discussionmentioning

confidence: 99%

Ether Lipid Deficiency in Mice Produces a Complex Behavioral Phenotype Mimicking Aspects of Human Psychiatric Disorders

Dorninger

Gundacker

Zeitler

et al. 2019

IJMS

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Ether lipids form a specialized subgroup of phospholipids that requires peroxisomes to be synthesized. We have previously detected that deficiency in these lipids leads to a severe disturbance of neurotransmitter homeostasis and release as well as behavioral abnormalities, such as hyperactivity, in a mouse model. Here, we focused on a more detailed examination of the behavioral phenotype of ether lipid-deficient mice (Gnpat KO) and describe a set of features related to human psychiatric disorders. Gnpat KO mice show strongly impaired social interaction as well as nestlet shredding and marble burying, indicating disturbed execution of inborn behavioral patterns. Also, compromised contextual and cued fear conditioning in these animals suggests a considerable memory deficit, thus potentially forming a connection to the previously determined ether lipid deficit in human patients with Alzheimer’s disease. Nesting behavior and the preference for social novelty proved normal in ether lipid-deficient mice. In addition, we detected task-specific alterations in paradigms assessing depression- and anxiety-related behavior. The reported behavioral changes may be used as easy readout for the success of novel treatment strategies against ether lipid deficiency in ameliorating nervous system-associated symptoms. Furthermore, our findings underline that ether lipids are paramount for brain function and demonstrate their relevance for cognitive, social, and emotional behavior. We hereby substantially extend previous observations suggesting a link between deficiency in ether lipids and human mental illnesses, particularly autism and attention-deficit hyperactivity disorder.

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Section: Discussionmentioning

confidence: 99%

Ether Lipid Deficiency in Mice Produces a Complex Behavioral Phenotype Mimicking Aspects of Human Psychiatric Disorders

Dorninger

Gundacker

Zeitler

et al. 2019

IJMS

View full text Add to dashboard Cite

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“…Furthermore, in environmental exposure models for ASD in rodents, n-3 PUFA or DHA supplementation were effective in reversing impairments in social interactions and elevation in social anxiety induced by maternal immune activation or exposure of food allergen during development [63,80,81]. Similarly, genetic models of ASD, including BTBR and serotonin transporter (SERT) knockout, demonstrated that pre-and postnatal n-3 PUFA or DHA supplementation may increase social interest and social preference for novel mice over objects as compared to mice fed n-3 PUFA deprived diets [82,83]. The improvements in social behaviors were observed in conjunction with higher DHA composition in the brain [82][83][84].…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, genetic models of ASD, including BTBR and serotonin transporter (SERT) knockout, demonstrated that pre-and postnatal n-3 PUFA or DHA supplementation may increase social interest and social preference for novel mice over objects as compared to mice fed n-3 PUFA deprived diets [82,83]. The improvements in social behaviors were observed in conjunction with higher DHA composition in the brain [82][83][84]. Therefore, dietary DHA intervention shows promising results for the prevention of the core behaviors associated with ASD in different animal models.…”

Section: Discussionmentioning

confidence: 99%

Loss of RAR-related orphan receptor alpha (RORα) selectively lowers docosahexaenoic acid in developing cerebellum

Chen

Schultz

Haven

et al. 2020

Prostaglandins, Leukotrienes and Essential Fatty Acids

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Deficiency in retinoid acid receptor-related orphan receptor alpha (RORα) of staggerer mice results in extensive granule and Purkinje cell loss in the cerebellum as well as in learned motor deficits, cognition impairments and perseverative tendencies that are commonly observed in autistic spectrum disorder (ASD). The effects of RORα on brain lipid metabolism associated with cerebellar atrophy remain unexplored. The aim of this study is to examine the effects of RORα deficiency on brain phospholipid fatty acid concentrations and compositions. Staggerer mice (Rora sg/sg) and wildtype littermates (Rora +/+) were fed n-3 polyunsaturated fatty acids (PUFA) containing diets ad libitum. At 2 months and 7 or more months old, brain total phospholipid fatty acids were quantified by gas chromatography-flame ionization detection. In the cerebellum, all fatty acid concentrations were reduced in 2 months old mice. Since total fatty acid concentrations were significantly different at 2-monthold, we examined changes in fatty acid composition. The composition of ARA was not significantly different between genotypes; though DHA composition remained significantly lowered. Despite cerebellar atrophy at >7months-old, cerebellar fatty acid concentrations had recovered comparably to wildtype control. Therefore, RORα may be necessary for fatty acid accretions during neurodevelopment. Specifically, the effects of RORα on PUFA metabolisms are region-specific and age-dependent.

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“…In a mouse model of ASD, in which animals are prenatally exposed to valproic acid, n-3 supplementation with both α- and γ-linolenic acid protected against the development of autistic-like features [ 296 ]. Besides, in an inbred mouse model of ASD (BTBR mouse strain), dietary deficiency in n-3 PUFAs from gestation to early adulthood induced developmental delay and altered sociability [ 297 ]. These results were also observed when these animals were fed with dietary n-3 PUFAs supplementation [ 297 ], suggesting that LC n-3 PUFAs cannot counterbalance the social deficits induced by such a genetic inbreeding.…”

Section: Role Of Pufas In Neurodevelopmental Diseasesmentioning

confidence: 99%

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

et al. 2021

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n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are provided by dietary intake. Growing evidence suggests that n-3 and n-6 PUFAs are paramount for brain functions. They constitute crucial elements of cellular membranes, especially in the brain. They are the precursors of several metabolites with different effects on inflammation and neuron outgrowth. Overall, long-chain PUFAs accumulate in the offspring brain during the embryonic and post-natal periods. In this review, we discuss how they accumulate in the developing brain, considering the maternal dietary supply, the polymorphisms of genes involved in their metabolism, and the differences linked to gender. We also report the mechanisms linking their bioavailability in the developing brain, their transfer from the mother to the embryo through the placenta, and their role in brain development. In addition, data on the potential role of altered bioavailability of long-chain n-3 PUFAs in the etiologies of neurodevelopmental diseases, such as autism, attention deficit and hyperactivity disorder, and schizophrenia, are reviewed.

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Chronic dietary changes in n-6/n-3 polyunsaturated fatty acid ratios cause developmental delay and reduce social interest in mice

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Cited by 15 publications

References 72 publications

Ether Lipid Deficiency in Mice Produces a Complex Behavioral Phenotype Mimicking Aspects of Human Psychiatric Disorders

Ether Lipid Deficiency in Mice Produces a Complex Behavioral Phenotype Mimicking Aspects of Human Psychiatric Disorders

Loss of RAR-related orphan receptor alpha (RORα) selectively lowers docosahexaenoic acid in developing cerebellum

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

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