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

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Liu, Ji-Hong, Wang, Qian, You, Qiang-Long, Li, Ze-Lin, Hu, Neng-Yuan, Wang, Yan, Jin, Zeng-Lin, Li, Shu-Ji +7 more·2020·Nature Communications
DOI 10.1038/s41467-020-19255-1PMC PMC7596714
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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-HT 6 R. Interestingly, DHA can prevent EPA-induced impairments at a ratio of EPA to DHA similar to that in marine fish oil via the 5-HT 2C R. 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.

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  1. [1]Bazinet RP Laye S Polyunsaturated fatty acids and their metabolites in brain function and disease Nat. Rev. Neurosci. 2014 15 771 785 25387473
  2. [2]Rapoport SI Rao JS Igarashi M Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver Prostaglandins Leukot. Essent. Fat. Acids 2007 77 251 261 PMC2725409 18060754
  3. [3]Rizos EC Ntzani E E. omega-3 Fatty acids and lutein + zeaxanthin supplementation for the prevention of cardiovascular disease JAMA Intern. Med. 2014 174 771 772 24638082
  4. [4]Saravanan P Davidson NC Schmidt EB Calder PC Cardiovascular effects of marine omega-3 fatty acids Lancet 2010 376 540 550 20638121
  5. [5]Yang ZH Emma-Okon B Remaley AT Dietary marine-derived long-chain monounsaturated fatty acids and cardiovascular disease risk: a mini review Lipids Health Dis. 2016 15 201 27876051 PMC5120510
  6. [6]Hallahan B Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression Br. J. Psychiatry 2016 209 192 201 27103682 PMC9406129
  7. [7]Lin PY Su KP A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids J. Clin. Psychiatry 2007 68 1056 1061 17685742
  8. [8]Lin P Huang S Su K A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression Biol. Psychiat. 2010 68 140 147 20452573
  9. [9]Lin PY Chang CH Chong MF Chen H Su KP Polyunsaturated fatty acids in perinatal depression: a systematic review and meta-analysis Biol. Psychiatry 2017 82 560 569 28410627
  10. [10]Frangou S Lewis M McCrone P Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study Br. J. Psychiatry 2006 188 46 50 16388069
  11. [11]Peet M Horrobin DF A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs Arch. Gen. Psychiatry 2002 59 913 919 12365878
  12. [12]Mischoulon D A double-blind, randomized controlled trial of ethyl-eicosapentaenoate for major depressive disorder J. Clin. Psychiatry 2009 70 1636 1644 19709502 PMC2918427
  13. [13]Mehta LR Dworkin RH Schwid SR Polyunsaturated fatty acids and their potential therapeutic role in multiple sclerosis Nat. Clin. Pract. Neurol. 2009 5 82 92 19194388
  14. [14]Belayev L Docosahexaenoic acid therapy of experimental ischemic stroke Transl. Stroke Res. 2011 2 33 41 21423332 PMC3037476
  15. [15]Stevens LJ Zentall SS Abate ML Kuczek T Burgess JR Omega-3 fatty acids in boys with behavior, learning, and health problems Physiol. Behav. 1996 59 915 920 8778886
  16. [16]Stevens LJ Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder Am. J. Clin. Nutr. 1995 62 761 768 7572706
  17. [17]Chang, J. P. et al. High-dose eicosapentaenoic acid (EPA) improves attention and vigilance in children and adolescents with attention deficit hyperactivity disorder (ADHD) and low endogenous EPA levels. Transl. Psychiatry. 9, 303 (2019). PMC6864068 31745072
  18. [18]McNamara RK Cognitive response to fish oil, blueberry, and combined supplementation in older adults with subjective cognitive impairment Neurobiol. Aging 2018 64 147 156 29458842 PMC5822748
  19. [19]Ghasemi FS Wang F Sinclair AJ Elliott G Turchini GM How does high DHA fish oil affect health? A systematic review of evidence Crit. Rev. Food Sci. Nutr. 2019 59 1684 1727 29494205
  20. [20]Quinn JF Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial JAMA 2010 304 1903 1911 21045096 PMC3259852
  21. [21]Yurko-Mauro K Cognitive and cardiovascular benefits of docosahexaenoic acid in aging and cognitive decline Curr. Alzheimer Res. 2010 7 190 196 20088810
  22. [22]Fotuhi M Mohassel P Yaffe K Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association Nat. Clin. Pract. Neurol. 2009 5 140 152 19262590
  23. [23]Lewis EJ Omega-3 fatty acid supplementation and cardiovascular disease events JAMA 2013 309 27 23280208
  24. [24]Vorhees CV Williams MT Morris water maze: procedures for assessing spatial and related forms of learning and memory Nat. Protoc. 2006 1 848 858 17406317 PMC2895266
  25. [25]Maren S Neurobiology of Pavlovian fear conditioning Annu. Rev. Neurosci. 2001 24 897 931 11520922
  26. [26]Bevins RA Besheer J Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study ‘recognition memory’ Nat. Protoc. 2006 1 1306 1311 17406415
  27. [27]Furuhashi M Hotamisligil GS Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets Nat. Rev. Drug Discov. 2008 7 489 503 18511927 PMC2821027
  28. [30]Bliss TV Collingridge GL A synaptic model of memory: long-term potentiation in the hippocampus Nature 1993 361 31 39 8421494
  29. [31]Mirnikjoo B Protein Kinase Inhibition by ω-3 Fatty Acids J. Biol. Chem. 2001 276 10888 10896 11152679
  30. [32]Kang JX Wang J Wu L Kang ZB Transgenic mice: fat-1 mice convert n-6 to n-3 fatty acids Nature 2004 427 504 14765186
  31. [33]Nicoll RA Malenka RC Expression mechanisms underlying NMDA receptor-dependent long-term potentiation Ann. N. Y Acad. Sci. 1999 868 515 525 10414328
  32. [34]Carroll RC Beattie EC von Zastrow M Malenka RC Role of AMPA receptor endocytosis in synaptic plasticity Nat. Rev. Neurosci. 2001 2 315 324 11331915
  33. [35]White JF Structure of the agonist-bound neurotensin receptor Nature 2012 490 508 513 23051748 PMC3482300
  34. [36]King MV Marsden CA Fone KC A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory Trends Pharmacol. Sci. 2008 29 482 492 19086256
  35. [38]Clark L Chamberlain SR Sahakian BJ Neurocognitive mechanisms in depression: implications for treatment Annu. Rev. Neurosci. 2009 32 57 74 19400725
  36. [39]Branchek TA Blackburn TP 5-ht6 receptors as emerging targets for drug discovery Annu Rev. Pharm. Toxicol. 2000 40 319 334 10836139
  37. [41]Sebben M Ansanay H Bockaert J Dumuis A 5-HT6 receptors positively coupled to adenylyl cyclase in striatal neurones in culture Neuroreport 1994 5 2553 2557 7696602
  38. [42]Bonasera, S. J., Chu, H., Brennan, T. J. & Tecott, L. H. A null mutation of the serotonin 6 receptor alters acute responses to ethanol. Neuropsychopharmacology. 31, 1801–1813 (2006). 16452990
  39. [43]Emery S Omega-3 and its domain-specific effects on cognitive test performance in youths: a meta-analysis Neurosci. Biobehav. Rev. 2020 112 420 436 32070694
  40. [44]Chew EY Effect of Omega-3 fatty acids, lutein/zeaxanthin, or other nutrient supplementation on cognitive function JAMA 2015 314 791 26305649 PMC5369607
  41. [45]Jerneren F Homocysteine Status modifies the treatment effect of omega-3 fatty acids on cognition in a randomized clinical trial in mild to moderate Alzheimer’s disease: The OmegAD Study J. Alzheimers Dis. 2019 69 189 197 30958356
  42. [46]Jiao J Effect of n-3 PUFA supplementation on cognitive function throughout the life span from infancy to old age: a systematic review and meta-analysis of randomized controlled trials Am. J. Clin. Nutr. 2014 100 1422 1436 25411277
  43. [47]Fujita S Ikegaya Y Nishikawa M Nishiyama N Matsuki N Docosahexaenoic acid improves long-term potentiation attenuated by phospholipase A(2) inhibitor in rat hippocampal slices Br. J. Pharmacol. 2001 132 1417 1422 11264234 PMC1572704
  44. [48]Bourre JM Dietary omega-3 Fatty acids and psychiatry: mood, behaviour, stress, depression, dementia and aging J. Nutr. Health Aging 2005 9 31 38 15750663
  45. [49]Bazan NG Molina MF Gordon WC Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer’s, and other neurodegenerative diseases Annu. Rev. Nutr. 2011 31 321 351 21756134 PMC3406932
  46. [50]Upton N Chuang TT Hunter AJ Virley DJ 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease Neurotherapeutics 2008 5 458 469 18625457 PMC5084247
  47. [51]Doody RS Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study Lancet 2008 372 207 215 18640457
  48. [52]Jones RW Dimebon disappointment Alzheimers Res. Ther. 2010 2 25 20836898 PMC2983434
  49. [53]Foley AG The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats Neuropharmacology 2008 54 1166 1174 18455201
  50. [54]Schechter LE Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466 Neuropsychopharmacology 2008 33 1323 1335 17625499
  51. [55]Del CS Jung M Lynch G Benzodiazepines block long-term potentiation in slices of hippocampus and piriform cortex Neuroscience 1992 49 1 6 1407540
  52. [56]Chiu CQ Compartmentalization of GABAergic inhibition by dendritic spines Science 2013 340 759 762 23661763 PMC3752161
  53. [57]Evans MC Rizwan MZ Anderson GM Insulin action on GABA neurons is a critical regulator of energy balance but not fertility in mice Endocrinology 2014 155 4368 4379 25116708
  54. [58]Zuure WA Roberts AL Quennell JH Anderson GM Leptin signaling in GABA neurons, but not glutamate neurons, is required for reproductive function J. Neurosci. 2013 33 17874 17883 24198376 PMC6618430
  55. [59]Di Giovanni G De Deurwaerdère P New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders Pharmacol. Ther. 2016 157 125 162 26617215
  56. [60]Hamano H Nabekura J Nishikawa M Ogawa T Docosahexaenoic acid reduces GABA response in substantia nigra neuron of rat J. Neurophysiol. 1996 75 1264 1270 8867135
  57. [61]Wigstrom H Gustafsson B Facilitated induction of hippocampal long-lasting potentiation during blockade of inhibition Nature 1983 301 603 604 6298626
  58. [62]Meredith RM Floyer-Lea AM Paulsen O Maturation of long-term potentiation induction rules in rodent hippocampus: role of GABAergic inhibition J. Neurosci. 2003 23 11142 11146 14657173 PMC6741060
  59. [63]McGahon BM Murray CA Horrobin DF Lynch MA Age-related changes in oxidative mechanisms and LTP are reversed by dietary manipulation Neurobiol. Aging 1999 20 643 653 10674430
  60. [64]McGahon BM Martin DS Horrobin DF Lynch MA Age-related changes in synaptic function: analysis of the effect of dietary supplementation with omega-3 fatty acids Neuroscience 1999 94 305 314 10613520
  61. [65]Lynch AM Eicosapentaenoic acid confers neuroprotection in the amyloid-β challenged aged hippocampus Neurobiol. Aging 2007 28 845 855 16714069
  62. [66]Lonergan PE Martin DSD Horrobin DF Lynch MA Neuroprotective actions of eicosapentaenoic acid on lipopolysaccharide-induced dysfunction in rat hippocampus J. Neurochem. 2004 91 20 29 15379883
  63. [67]Lonergan PE Martin DSD Horrobin DF Lynch MA Neuroprotective Effect of Eicosapentaenoic Acid in Hippocampus of Rats Exposed to γ-Irradiation J. Biol. Chem. 2002 277 20804 20811 11912218
  64. [68]Orr SK Unesterified docosahexaenoic acid is protective in neuroinflammation J. Neurochem. 2013 127 378 393 23919613 PMC4068707
  65. [69]Delpech JC Transgenic increase in n-3/n-6 fatty acid ratio protects against cognitive deficits induced by an immune challenge through decrease of neuroinflammation Neuropsychopharmacology 2015 40 525 536 25228141 PMC4289942
  66. [70]Hopperton KE Trépanier M James NCE Chouinard-Watkins R Bazinet RP Fish oil feeding attenuates neuroinflammatory gene expression without concomitant changes in brain eicosanoids and docosanoids in a mouse model of Alzheimer’s disease Brain, Behav., Immun. 2018 69 74 90 29109025
  67. [71]Jašarević E Hecht PM Fritsche KL Beversdorf DQ Geary DC Dissociable effects of dorsal and ventral hippocampal DHA content on spatial learning and anxiety-like behavior Neurobiol. Learn. Mem. 2014 116 59 68 25180934
  68. [72]Nishi D The synchronized trial on expectant mothers with depressive symptoms by omega-3 PUFAs (SYNCHRO): Study protocol for a randomized controlled trial BMC Psychiatry 2016 16 321 27630014 PMC5024529
  69. [73]Tian J Down-regulation of Neuregulin1/ErbB4 signaling in the hippocampus is critical for learning and memory Mol. Neurobiol. 2017 54 3976 3987 27295274
  70. [74]Chen Y ErbB4 signaling in the prelimbic cortex regulates fear expression Transl. Psychiat. 2017 7 e1168 PMC5538119 28675393
  71. [75]Liu JH Social isolation during adolescence strengthens retention of fear memories and facilitates induction of late-phase long-term potentiation Mol. Neurobiol. 2015 52 1421 1429 25860250 PMC4588096
  72. [76]Liu JH Astrocytic GABAB receptors in mouse hippocampus control responses to behavioral challenges through astrocytic BDNF Neurosci. Bull. 2020 36 705 718 32166647 PMC7340691
  73. [77]Deacon RMJ Rawlins JNP T-maze alternation in the rodent Nat. Protoc. 2006 1 7 12 17406205
  74. [78]Lin S Social isolation during adolescence induces anxiety behaviors and enhances firing activity in BLA pyramidal neurons via mGluR5 upregulation Mol. Neurobiol. 2018 55 5310 5320 28914419
  75. [79]Kang JX Wang J A simplified method for analysis of polyunsaturated fatty acids BMC Biochem. 2005 6 5 15790399 PMC1079797
  76. [80]Xue R Antidepressant-like effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor Eur. Neuropsychopharmacol. 2013 23 728 741 22748419
  77. [81]Li B Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling Nat. Neurosci. 2014 17 1055 1063 24952642 PMC4115017
  78. [82]Cao X Astrocyte-derived ATP modulates depressive-like behaviors Nat. Med. 2013 19 773 777 23644515
  79. [83]Van Schoors J Reassessment of the antioxidative mixture for the challenging electrochemical determination of dopamine, noradrenaline and serotonin in microdialysis samples J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2015 998-999 63 71 26177328

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Authors
Liu, J.-H., Wang, Q., You, Q.-L., Li, Z.-L., Hu, N.-Y., Wang, Y., Jin, Z.-L., Li, S.-J., Li, X.-W., Yang, J.-M., Zhu, X.-H., Dai, Y.-F., Xu, J.-P., Bai, X.-C., & Gao, T.-M.
Affiliations
  • Southern Medical University (CN)
  • State Key Laboratory of Reproductive Medicine (CN)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-10-29
Volume
11
Issue
1
Pages
5465-5465
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-19255-1
PMC
PMC7596714
OpenAlex
W3097623532
Cited by
77
References
5
Citations by year
2026: 9 · 2025: 11 · 2024: 15 · 2023: 16 · 2022: 14 · 2021: 11 · 2020: 1
FWCI
6.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (31430032)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
eicosapentaenoic acid, docosahexaenoic acid, omega-3 fatty acids, learning and memory impairment, hippocampal long-term potentiation, GABAergic neurotransmission, 5-HT6 receptor, 5-HT2C receptor, fat-1 transgenic mice, synaptic plasticity, cognitive function, fatty acid supplementation, marine fish oil
MeSH terms
Animals, Cognition, Docosahexaenoic Acids, Drug Combinations, Fish Oils, Humans, Learning, Memory Disorders, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Dietary Supplements, Receptor, Serotonin, 5-HT2C, Mice, GABAergic Neurons

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