Cited by 144Epigenetics and DNA MethylationTryptophan and brain disordersMaternal Mental Health During Pregnancy and Postpartum

Maternal immune activation induces GAD1 and GAD2 promoter remodeling in the offspring prefrontal cortex

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Labouesse, Marie Anaïs, Dong, Erbo, Grayson, Dennis Robert, Guidotti, Alessandro, Meyer, Urs·2015·Epigenetics

Abstract

Maternal infection during pregnancy increases the risk of neurodevelopmental disorders in the offspring. In addition to its influence on other neuronal systems, this early-life environmental adversity has been shown to negatively affect cortical γ-aminobutyric acid (GABA) functions in adult life, including impaired prefrontal expression of enzymes required for GABA synthesis. The underlying molecular processes, however, remain largely unknown. In the present study, we explored whether epigenetic modifications represent a mechanism whereby maternal infection during pregnancy can induce such GABAergic impairments in the offspring. We used an established mouse model of prenatal immune challenge that is based on maternal treatment with the viral mimetic poly(I:C). We found that prenatal immune activation increased prefrontal levels of 5-methylated cytosines (5mC) and 5-hydroxymethylated cytosines (5hmC) in the promoter region of GAD1, which encodes the 67-kDa isoform of the GABA-synthesising enzyme glutamic acid decarboxylase (GAD67). The early-life challenge also increased 5mC levels at the promoter region of GAD2, which encodes the 65-kDa GAD isoform (GAD65). These effects were accompanied by elevated GAD1 and GAD2 promoter binding of methyl CpG-binding protein 2 (MeCP2) and by reduced GAD67 and GAD65 mRNA expression. Moreover, the epigenetic modifications at the GAD1 promoter correlated with prenatal infection-induced impairments in working memory and social interaction. Our study thus highlights that hypermethylation of GAD1 and GAD2 promoters may be an important molecular mechanism linking prenatal infection to presynaptic GABAergic impairments and associated behavioral and cognitive abnormalities in the offspring.

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  • Labouesse et al. found that a single poly(I:C) injection increased 5-methylcytosine and 5-hydroxymethylcytosine on the GAD1 promoter, and these changes correlated with social interaction and working memory impairments.

    “A 2015 epigenetic study also using a single poly (I:C) injection found significantly increased rates of 5-methylcytosine and 5-hydroxymethylcytosine on the glutamic acid decarboxylase (GAD1) promoter”

    From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Labouesse et al, 2015

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Authors
Labouesse, M. A., Dong, E., Grayson, D. R., Guidotti, A., & Meyer, U.
Affiliations
  • ETH Zurich (CH)
  • University of Illinois Chicago (US)
  • University of Zurich (CH)
Corresponding author
Labouesse, Marie Anaïs
Venue
Epigenetics
Published
2015-12-02
Volume
10
Issue
12
Pages
1143-1155
ISSN
  • 1559-2294 (ISSN-L)
  • 1559-2308
OpenAlex
W2219458178
Cited by
138
References
87
Citations by year
2026: 5 · 2025: 10 · 2024: 19 · 2023: 11 · 2022: 17 · 2021: 10 · 2020: 13 · 2019: 13 · 2018: 12 · 2017: 14 · 2016: 13
FWCI
5.64
Type
journal article
Language
en
Open access
Locations
  • Epigenetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation (259679)
  • European Molecular Biology Organization
  • European Commission (FP7/2007-2011, FP7/2007, 259679)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (146217, FP7/2007-2011)
  • National Institutes of Health
  • U.S. Public Health Service (NIMH2013-00362)
  • National Institute of Mental Health (R01MH093348)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
Keywords
maternal immune activation, prenatal infection, poly(I:C), GAD1, GAD-2, glutamic acid decarboxylase, GABA synthesis, prefrontal cortex, DNA methylation, 5-hydroxymethylcytosine, MeCP2, epigenetic regulation, working memory, social interaction, neurodevelopmental disorders, childhood adversity
MeSH terms
Animals, Binding Sites, Female, Glutamate Decarboxylase, Immunity, Innate, Pregnancy, Prenatal Exposure Delayed Effects, Promoter Regions, Genetic, RNA, Messenger, Prefrontal Cortex, DNA Methylation, Epigenesis, Genetic, Mice, Methyl-CpG-Binding Protein 2

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