Acute EPA-induced learning and memory impairment in mice is prevented by DHA

Zeng-Lin Jin,Xin-Hong Zhu,Jian-Ming Yang,Neng-Yuan Hu,Qian Wang,Jiang-Ping Xu,Yan Wang,Shu-Ji Li,Tian-Ming Gao,Ji-Hong Liu,Qiang-Long You,Xiao-Chun Bai,Ze-Lin Li,Xiao-Wen Li,Yi-Fan Dai

doi:10.1038/s41467-020-19255-1

Zeng-Lin Jin, Xin-Hong Zhu + Show 13 more

Open Access

https://doi.org/10.1038/s41467-020-19255-1

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Abstract

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been widely used to prevent cardiovascular disease (CVD) and treat brain diseases alone or in combination with docosahexaenoic acid (DHA). However, the impact of EPA and DHA supplementation on normal cognitive function and the molecular targets of EPA and DHA are still unknown. We show that acute administration of EPA impairs learning and memory and hippocampal LTP in adult and prepubescent mice. Similar deficits are duplicated by endogenously elevating EPA in the hippocampus in the transgenic fat-1 mouse. Furthermore, the damaging effects of EPA are mediated through enhancing GABAergic transmission via the 5-HT6R. Interestingly, DHA can prevent EPA-induced impairments at a ratio of EPA to DHA similar to that in marine fish oil via the 5-HT2CR. We conclude that EPA exhibits an unexpected detrimental impact on cognitive functions, suggesting that caution must be exercised in omega-3 fatty acid supplementation and the combination of EPA and DHA at a natural ratio is critical for learning and memory and synaptic plasticity.

Highlights

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been widely used to prevent cardiovascular disease (CVD) and treat brain diseases alone or in combination with docosahexaenoic acid (DHA)
We found that compared to mice that did not receive EPA, EPA-treated mice exhibited impaired learning and memory, with poorer learning ability and memory performance in the Morris water maze (MWM) (Fig. 1a–e), a shorter freezing duration in contextual fear conditioning (Fig. 1f) and a lack of preference in novel object recognition (NOR) (Fig. 1g)
Gas chromatography (GC) results indicated that EPA treatment (50 mg/kg) significantly increased the level of that fatty acid in the hippocampus but not in the prefrontal cortex (PFC) or striatum (Fig. 1h), which may be due to hippocampal enrichment of fatty acid-binding protein 7 (FABP7) (Supplementary Fig. 1h), a protein that binds omega-3 fatty acids with high affinity and stores them[27]

Summary

Introduction

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been widely used to prevent cardiovascular disease (CVD) and treat brain diseases alone or in combination with docosahexaenoic acid (DHA). Similar to essential amino acids, some fatty acids are essential for the human body because mammals cannot generate them de novo, relying instead on a constant supply of food[1] These fatty acids are long-chain polyunsaturated fatty acids found in various plant and marine life as the precursors linoleic acid and αlinolenic acid and are metabolized by elongation and desaturation into omega-3 fatty acids, such as arachidonic acid (AA), EPA, and DHA in mammals[2]. In addition to the beneficial effects of omega-3 fatty acids on peripheral organ disorders such as CVD, studies focusing on the brain have found that supplementation with DHA and EPA can alleviate disease of the central nervous system. Little is known about the effect of EPA and DHA supplementation on normal cognitive function or the molecular target of omega-3 fatty acids in brain

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