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Cited by 37Folate and B Vitamins ResearchEpigenetics and DNA MethylationMemory and Neural Mechanisms

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Methyl Donor-Deficient Diet during Development Can Affect Fear and Anxiety in Adulthood in C57BL/6J Mice

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Ishii, Daisuke, Matsuzawa, Daisuke, Matsuda, Shingo, Tomizawa, Haruna, Sutoh, Chihiro, Shimizu, Eiji·2014·PLoS ONE
DOI 10.1371/journal.pone.0105750PMC PMC4140817
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Abstract

DNA methylation is one of the essential factors in the control of gene expression. Folic acid, methionine and choline (methyl donors)--all nutrients related to one-carbon metabolism--are known as important mediators of DNA methylation. A previous study has shown that long-term administration of a diet lacking in methyl donors caused global DNA hypermethylation in the brain (Pogribny et al., 2008). However, no study has investigated the effects of a diet lacking in methyl donors during the developmental period on emotional behaviors such as fear and anxiety-like behavior in association with gene expressions in the brain. In addition, it has not been elucidated whether a diet supplemented with methyl donors later in life can reverse these changes. Therefore, we examined the effects of methyl donor deficiency during the developmental period on fear memory acquisition/extinction and anxiety-like behavior, and the relevant gene expressions in the hippocampus in juvenile (6-wk) and adult (12-wk) mice. We found that juvenile mice fed a methyl-donor-deficient diet had impaired fear memory acquisition along with decreases in the gene expressions of Dnmt3a and Dnmt3b. In addition, reduced anxiety-like behavior with decreased gene expressions of Grin2b and Gabar2 was observed in both the methyl-donor-deficient group and the body-weight-matched food-restriction group. After being fed a diet supplemented with methyl donors ad libitum, adult mice reversed the alteration of gene expression of Dnmt3a, Dnmt3b, Grin2b and Gabar2, but anxiety-like behavior became elevated. In addition, impaired fear-memory formation was observed in the adult mice fed the methyl-donor-deficient diet during the developmental period. Our study suggested that developmental alterations in the one-carbon metabolic pathway in the brain could have effects on emotional behavior and memory formation that last into adulthood.

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  • DNMTs play a role in fear memory consolidation and plasticity in the hippocampus at younger ages, possibly forming the core psychopathology of inappropriate anxiety responses that may carry into adulthood.

    “This particular study highlights the role of DNMTs in fear memory consolidation and plasticity in the hippocampus at younger ages, possibly forming the core psychopathology of inappropriate anxiety responses that may carry into adulthood (Ishii et al., 2014).”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Ishii et al., 2014

    The Discussion suggests that Dnmts play a role in hippocampal fear-memory acquisition in juvenile mice and that developmental methyl-donor deficiency may leave fear memory impaired in adulthood. It cites earlier work for a link between Dnmt inhibition and hippocampal synaptic plasticity, but does not establish that Dnmt-related consolidation or plasticity forms the basis of adult anxiety; its discussion of a possible substrate for that anxiety instead concerns GABAA receptor changes. The Results report reduced hippocampal Dnmt3a and Dnmt3b expression at 6 weeks, but not at 12 weeks. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Knockdown of Dnmt3a in the mPFC of rats resulted in an anxiety-like phenotype, contrary to the reduced anxiety behaviors observed following decreased Dnmt3a expression in the mouse hippocampus.

    “Last, knockdown of Dnmt3a in the mPFC of rats resulted in an anxiety-like phenotype in the study by Elliott et al. (2016), contrary to the reduced anxiety behaviors observed following a decrease in Dnmt3a expression in the mouse hippocampus in the research of Ishii et al. (2014).”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Ishii et al., 2014

    The Results report lower hippocampal Dnmt3a expression in methyl-donor-deficient juvenile mice, and the Discussion reports reduced anxiety-like behavior in those mice. Ishii et al. do not establish that the expression decrease caused the behavioral change: the diet also reduced Dnmt3b expression, and food restriction likewise reduced anxiety-like behavior. The rat mPFC finding is attributed to Elliott et al., not to this source. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • DNMT1 levels were unaffected in low methyl-fed mice.

    “and DNMT1 levels were unaffected in low methyl-fed mice (Ishii et al., 2014).”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Ishii et al., 2014

    The Results section (“Expression levels of Dnmts in the hippocampus”; page not specified) reports no significant difference in Dnmt1 expression among groups at 6 or 12 weeks. The Methods section shows this was an mRNA measurement from the dorsal hippocampus, so it does not establish that DNMT1 protein levels were unaffected throughout the mice. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The Ye et al. (2018) iron study failed to investigate levels of Dnmt3a and Dnmt3b, and the Ishii et al. (2014) study failed to correlate decreases in Gabra2 levels with detected GABA levels.

    “While the Ye et al. (2018) iron study failed to investigate levels of Dnmt3a and Dnmt3b, the study by Ishii et al. (2014) failed to correlate decreases in Gabra2 levels with detected GABA levels.”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Ishii et al., 2014

    The Results section on gene expression in juvenile mice reports decreased Gabra2 expression at six weeks. The cited copy does not report measured GABA levels or a correlation between those levels and Gabra2 expression, so the claim’s reference to ‘detected GABA levels’ is unsupported. The statement about Ye et al. is not attributed to Ishii et al. and is not assessed here. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Dnmt3a and Dnmt3b reduction does not explain the decrease in Gabra2 levels in low methyl-fed mice.

    “Furthermore, though Dnmt3a and Dnmt3b showed significant reduction in expression, these levels do not explain a decrease in Gabra2 levels, and DNMT1 levels were unaffected in low methyl-fed mice (Ishii et al., 2014).”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Ishii et al., 2014

    The Results (pages not provided) report significantly lower Dnmt3a and Dnmt3b expression in methyl-donor-deficient mice at 6 weeks, lower Gabra2 expression in both the deficient and food-restricted groups, and no significant difference in Dnmt1 expression. The paper does not conclude that reduced Dnmt3a and Dnmt3b cannot explain the Gabra2 decrease in the methyl-donor-deficient mice; that mechanistic conclusion goes beyond the reported results. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Metadata

Authors
Ishii, D., Matsuzawa, D., Matsuda, S., Tomizawa, H., Sutoh, C., & Shimizu, E.
Affiliations
Chiba University (JP)
Corresponding author
Ishii, Daisuke
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-08-21
Volume
9
Issue
8
Pages
e105750
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0105750
PMC
PMC4140817
OpenAlex
W2019239098
Cited by
37
References
59
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 5 · 2015: 3
FWCI
3.88
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Chiba University
  • Japan Society for the Promotion of Science (26860912, 24791196)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
methyl donor deficiency, one-carbon metabolism, DNA methylation, folic acid, methionine, choline, fear memory, anxiety-like behavior, fear extinction, DNMT3A, DNMT3B, NR2B subunit, hippocampus, dietary supplementation, emotional behavior, C57BL/6J mice
MeSH terms
DNA Methyltransferase 3A, DNA Methyltransferase 3B, Animals, Anxiety, Behavior, Animal, Diet, DNA (Cytosine-5-)-Methyltransferases, Fear, Female, Gene Expression Regulation, Hippocampus, Male, Receptors, N-Methyl-D-Aspartate, DNA Methylation, Mice

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