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Cited by 32Epigenetics and DNA MethylationStress Responses and CortisolMaternal Mental Health During Pregnancy and Postpartum

Involvement of Epigenetic Modifications of GABAergic Interneurons in Basolateral Amygdala in Anxiety-like Phenotype of Prenatally Stressed Mice

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Zhu, Chunting, Liang, Min, Li, Yingchun, Feng, Xuejiao, Hong, Juan, Zhou, Rong·2018·International Journal of Neuropsychopharmacology
DOI 10.1093/ijnp/pyy006PMC PMC6007574
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Abstract

Background: Prenatal stress is considered a risk factor for anxiety disorder. Downregulation in the expression of GABAergic gene, that is, glutamic acid decarboxylase 67, associated with DNA methyltransferase overexpression in GABAergic neurons has been regarded as a characteristic component of anxiety disorder. Prenatal stress has an adverse effect on the development of the basolateral amygdala, which is a key region in anxiety regulation. The aim of this study is to analyze the possibility of epigenetic alterations of GABAergic neurons in the basolateral amygdala participating in prenatal stress-induced anxiety. Methods: Behavioral tests were used to explore the prenatal stress-induced anxiety behaviors of female adult mice. Real-time RT-PCR, western blot, chromatin immunoprecipitation, and electrophysiological analysis were employed to detect epigenetic changes of GABAergic system in the basolateral amygdala. Results: Prenatal stress mice developed an anxiety-like phenotype accompanied by a significant increase of DNA methyltransferase 1 and a reduced expression of glutamic acid decarboxylase 67 in the basolateral amygdala. Prenatal stress mice also showed the increased binding of DNA methyltransferase 1 and methyl CpG binding protein 2 to glutamic acid decarboxylase 67 promoter region. The decrease of glutamic acid decarboxylase 67 transcript was paralleled by an enrichment of 5-methylcytosine in glutamic acid decarboxylase 67 promoter regions. Electrophysiological study revealed the increase of postsynaptic neuronal excitability in the cortical-basolateral amygdala synaptic transmission of prenatal stress mice. 5-Aza-deoxycytidine treatment restored the increased synaptic transmission and anxiety-like behaviors in prenatal stress mice via improving GABAergic system. Conclusion: The above results suggest that DNA epigenetic modifications of GABAergic interneurons in the basolateral amygdala participate in the etiology of anxiety-like phenotype in prenatal stress mice.

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  • On stimulation of the entorhinal cortex, PRS mice displayed a greater number of population spikes in the BLA.

    “Most interestingly, these researchers conducted electrophysiological analysis on brain slices of PRS and control mice and found that on stimulation of the entorhinal cortex, PRS mice displayed a greater number of population spikes in the BLA.”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Zhu et al., 2018

    The Methods (Electrophysiological Analysis; page unavailable) identify EC as the external capsule and say stimulation was applied there, not to the entorhinal cortex. The Results report that this stimulation evoked significantly more population spikes in BLA slices from PRS mice than from controls, but the claimed stimulation site is wrong. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • There is a direct relationship between decreased mRNA levels of GAD67, repressed by promoter hypermethylation, and overexpressed Dnmt1 with increased methylating activity.

    “This provided a direct relationship between the decreased mRNA levels of GAD67 (repressed by promoter hypermethylation) and overexpressed Dnmt1 (increased methylating activity), as well as underscoring a direct role of prenatal stressors in utero and later observed anxiety phenotypes in offspring (Zhu et al., 2018).”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Zhu et al., 2018

    The Results sections report elevated DNMT1 expression and binding at the GAD67 promoter, increased promoter methylation, and an inverse correlation between methylation and GAD67 transcripts in prenatally stressed mice. The Discussion proposes a DNMT1-regulated mechanism, but the paper does not report a direct assay of increased DNMT1 methylating activity; that parenthetical overstates the evidence. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • PRS offspring displayed similar anxiety-like behaviors as BPA-treated mice.

    “Using a prenatal restraint stress (PRS) model on pregnant dams, researchers found that PRS offspring displayed similar anxiety-like behaviors as BPA-treated mice, as well as an increased binding of overexpressed Dnmt1 to the promoter region of Gad67 (along with MeCP2, discussed later).”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Zhu et al., 2018

    The Results section, “PRS Mice Express the Increase of Anxiety-like Behaviors in Behavioral Experiments” (page unavailable), reports increased anxiety-like behaviors in PRS offspring compared with controls. The paper does not report a BPA-treated group or compare its behaviors with those of PRS offspring, so the claimed similarity is unsupported. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • A decrease in GAD67 expression impairs GABAergic pathways, which in turn fail to inhibit glutamatergic or excitatory pathways in the BLA.

    “These findings were attributed to higher neuronal firing rates and cortical–BLA synaptic activity, suggesting that a decrease in GAD67 expression impairs GABAergic pathways, which in turn fail to inhibit glutamatergic or excitatory pathways in the BLA (Zhu et al., 2018).”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Zhu et al., 2018

  • PRS offspring had increased binding of overexpressed Dnmt1 to the promoter region of Gad67.

    “as well as an increased binding of overexpressed Dnmt1 to the promoter region of Gad67 (along with MeCP2, discussed later).”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Zhu et al., 2018

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Cited by

Sorted by citations

Authors
Zhu, C., Liang, M., Li, Y., Feng, X., Hong, J., & Zhou, R.
Affiliations
Nanjing Medical University (CN)
Corresponding author
Zhou, Rong
ORCID
Venue
International Journal of Neuropsychopharmacology
Publisher
Oxford University Press (OUP)
Published
2018-02-20
Volume
21
Issue
6
Pages
570-581
ISSN
  • 1461-1457 (ISSN-L)
  • 1469-5111
DOI
10.1093/ijnp/pyy006
PMC
PMC6007574
OpenAlex
W2793095131
Cited by
32
References
4
Citations by year
2026: 4 · 2025: 7 · 2024: 1 · 2023: 5 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 3
FWCI
0.98
Type
journal article
Language
en
Open access
Licence
Locations
  • The International Journal of Neuropsychopharmacology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81471385)
  • Natural Science Foundation of Jiangsu Province (BK20151552)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
Keywords
prenatal stress, anxiety-like behavior, basolateral amygdala, GABAergic interneurons, DNA methylation, DNMT1, glutamic acid decarboxylase 67, MeCP2, 5-methylcytosine, postsynaptic excitability, 5-aza-deoxycytidine
MeSH terms
DNA (Cytosine-5-)-Methyltransferase 1, Animals, Anxiety, Anxiety Disorders, Disease Models, Animal, Female, Glutamate Decarboxylase, Interneurons, Mice, Inbred C57BL, Phenotype, Pregnancy, Prenatal Exposure Delayed Effects, Promoter Regions, Genetic, Stress, Psychological, DNA Methylation, Tissue Culture Techniques, GABAergic Neurons, Basolateral Nuclear Complex

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