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Maternal immune activation induces GAD1 and GAD2 promoter remodeling in the offspring prefrontal cortex
Open accessAbstract
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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“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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Metadata
- 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
- Publisher
- Informa UK Limited
- Published
- 2015-12-02
- Volume
- 10
- Issue
- 12
- Pages
- 1143-1155
- ISSN
- 1559-2294 (ISSN-L)
- 1559-2308
- PMC
- PMC4844233
- 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
- bronze
- doi.org
- 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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