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Cited by 271Epigenetics and DNA MethylationSchizophrenia research and treatmentMaternal Mental Health During Pregnancy and Postpartum

Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice

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Matrisciano, Francesco, Tueting, Patricia, Dalal, Ishani, Kadriu, Bashkim, Grayson, Dennis R., Davis, John M., Nicoletti, Ferdinando, Guidotti, Alessandro·2013·Neuropharmacology
DOI 10.1016/j.neuropharm.2012.04.013PMC PMC3433586
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Abstract

Human studies suggest that a variety of prenatal stressors are related to high risk for cognitive and behavioral abnormalities associated with psychiatric illness (Markham and Koenig, 2011). Recently, a downregulation in the expression of GABAergic genes (i.e., glutamic acid decarboxylase 67 and reelin) associated with DNA methyltransferase (DNMT) overexpression in GABAergic neurons has been regarded as a characteristic phenotypic component of the neuropathology of psychotic disorders (Guidotti et al., 2011). Here, we characterized mice exposed to prenatal restraint stress (PRS) in order to study neurochemical and behavioral abnormalities related to development of schizophrenia in the adult. Offspring born from non-stressed mothers (control mice) showed high levels of DNMT1 and 3a mRNA expression in the frontal cortex at birth, but these levels progressively decreased at post-natal days (PND) 7, 14, and 60. Offspring born from stressed mothers (PRS mice) showed increased levels of DNMTs compared to controls at all time-points studied including at birth and at PND 60. Using GAD67-GFP transgenic mice, we established that, in both control and PRS mice, high levels of DNMT1 and 3a were preferentially expressed in GABAergic neurons of frontal cortex and hippocampus. Importantly, the overexpression of DNMT in GABAergic neurons was associated with a decrease in reelin and GAD67 expression in PRS mice in early and adult life. PRS mice also showed an increased binding of DNMT1 and MeCP2, and an increase in 5-methylcytosine and 5-hydroxymethylcytosine in specific CpG-rich regions of the reelin and GAD67 promoters. Thus, the epigenetic changes in PRS mice are similar to changes observed in the post-mortem brains of psychiatric patients. Behaviorally, adult PRS mice showed hyperactivity and deficits in social interaction, prepulse inhibition, and fear conditioning that were corrected by administration of valproic acid (a histone deacetylase inhibitor) or clozapine (an atypical antipsychotic with DNA-demethylation activity). Taken together, these data show that prenatal stress in mice induces abnormalities in the DNA methylation network and in behaviors indicative of a schizophrenia-like phenotype. Thus, PRS mice may be a valid model for the investigation of new drugs for schizophrenia treatment targeting DNA methylation. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.

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  • Early-life trauma in rodent models can influence DNA methylation of various candidate genes in brain regions important in stress signaling.

    “Numerous subsequent studies using rodent models have shown that early-life trauma (e.g., chronic and unpredictable maternal behavior, separation, fear conditioning), can influence DNA methylation of various candidate genes in brain regions important in stress signaling.”

    From Biological Embedding of Early-Life Adversity and a Scoping Review of the Evidence for Intergenerational Epigenetic Transmission of Stress and Trauma in Humans (2023) · cites this paper as [39]

    The Results (§3.4; page unavailable) show increased methylation-related modifications at the reelin and GAD67 promoters in the frontal cortex of mice exposed to prenatal restraint stress. This supports the general link between early stress and altered DNA methylation in rodent brain, but the paper does not study the cited examples of maternal behavior, separation, or fear conditioning as stress exposures, or identify these genes as stress-signaling genes. (LLM, conf=0.86)

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  • Other candidate genes shown to be differentially methylated in rodent models include reelin (Reln), corticotropin-releasing hormone receptor (Crh), and arginine vasopressin gene (Avp).

    “Other candidate genes shown to be differentially methylated include reelin (Reln) [39], which is involved in neurogenesis and synaptic plasticity, corticotropin-releasing hormone receptor (Crh) [40], which binds corticotropin-releasing hormone and plays an important role in stress signaling, and arginine vasopressin gene (Avp) [41].”

    From Biological Embedding of Early-Life Adversity and a Scoping Review of the Evidence for Intergenerational Epigenetic Transmission of Stress and Trauma in Humans (2023) · cites this paper as [39]

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Authors
Matrisciano, F., Tueting, P., Dalal, I., Kadriu, B., Grayson, D. R., Davis, J. M., Nicoletti, F., & Guidotti, A.
Affiliations
  • University of Illinois Chicago (US)
  • Istituto Neurologico Mediterraneo (IT)
Corresponding author
Matrisciano, Francesco
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2013-05
Volume
68
Pages
184-194
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2012.04.013
PMC
PMC3433586
OpenAlex
W2047021875
Cited by
271
References
7
Citations by year
2026: 8 · 2025: 6 · 2024: 10 · 2023: 16 · 2022: 20 · 2021: 22 · 2020: 17 · 2019: 15 · 2018: 23 · 2017: 25 · 2016: 28 · 2015: 23 · 2014: 36 · 2013: 15 · 2012: 7
FWCI
10.55
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (R01MH093348, MH0708551)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
Keywords
prenatal stress, schizophrenia, GABAergic interneurons, DNA methylation, DNMT1, DNMT3A, GAD67, reelin, MeCP2, 5-hydroxymethylcytosine, 5-methylcytosine, promoter CpG methylation, restraint stress, hyperactivity, prepulse inhibition, social interaction deficits, fear conditioning, valproic acid, clozapine, histone deacetylase inhibition, schizophrenia model, frontal cortex, hippocampus
MeSH terms
DNA (Cytosine-5-)-Methyltransferase 1, Reelin Protein, Animals, Behavior, Animal, Disease Models, Animal, DNA (Cytosine-5-)-Methyltransferases, Female, Frontal Lobe, Glutamate Decarboxylase, Hippocampus, Interneurons, Motor Activity, Nerve Tissue Proteins, Phenotype, Pregnancy, Prenatal Exposure Delayed Effects, Restraint, Physical, RNA, Messenger, Schizophrenia, Serine Endopeptidases, Social Behavior, Stress, Physiological, Stress, Psychological, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Mice, GABAergic Neurons

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