Neonatal Maternal Separation Alters the Capacity of Adult Neural Precursor Cells to Differentiate into Neurons Via Methylation of Retinoic Acid Receptor Gene Promoter
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Background Early life stress is thought to contribute to psychiatric disorders, but the precise mechanisms underlying this link are poorly understood. As neonatal stress decreases adult hippocampal neurogenesis, which, in turn, functionally contributes to many behavioral phenotypes relevant to psychiatric disorders, we examined how in vivo neonatal maternal separation (NMS) impacts the capacity of adult hippocampal neural precursor cells via epigenetic alterations in vitro.Methods Rat pups were separated from their dams for 3 hours daily from postnatal day (PND) 2 to PND 14 or were never separated from the dam (as control animals). We isolated adult neural precursor cells from the hippocampal dentate gyrus at PND 56 and assessed rates of proliferation, apoptosis, and differentiation in cell culture. We also evaluated the effect of DNA methylation at the retinoic acid receptor (RAR) promoter stemming from NMS on adult neural precursor cells.Results NMS attenuated neural differentiation of adult neural precursor cells but had no detectible effect on proliferation, apoptosis, or astroglial differentiation. The DNA methyltransferase (DNMT) inhibitor, 5-aza-dC, reversed a reduction by NMS of neural differentiation of adult neural precursor cells. NMS increased DNMT1 expression and decreased expression of RARα. An RARα agonist increased neural differentiation and an antagonist reduced retinoic acid-induced neural differentiation. NMS increased the methylated portion of RARα promoter, and the DNMT inhibitor reversed a reduction by NMS of RARα messenger RNA expression.Conclusions NMS attenuates the capacity of adult hippocampal neural precursor cells to differentiate into neurons by decreasing expression of RARα through DNMT1-mediated methylation of its promoter.
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Retinoic acid receptor promoter CpG island methylation is increased in adult neural precursor cells isolated from the dentate gyrus of adult male rats that underwent neonatal maternal separation.
“Retinoic acid receptor, also critical to neurodevelopment, specifically neural differentiation, was found in another study to have increased promoter CpG island methylation in adult neural precursor cells isolated from the dentate gyrus of adult male rats (females unexamined) that underwent neonatal maternal separation (MS) [102].”
From Cell-type-specific epigenetic effects of early life stress on the brain (2022) · cites this paper as [102]
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- Authors
- Boku, S., Toda, H., Nakagawa, S., Kato, A., Inoue, T., Koyama, T., Hiroi, N., & Kusumi, I.
- Affiliations
- Albert Einstein College of Medicine (US)
- Hokkaido University (JP)
- Corresponding author
- Boku, Shuken
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 77
- Issue
- 4
- Pages
- 335-344
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5241093
- OpenAlex
- W2031913576
- Cited by
- 56
- References
- 60
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 11 · 2016: 8 · 2015: 6
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Hokkaido University Collection of Scholarly and Academic Papers (Hokkaido University) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- SENSHIN Medical Research Foundation
- National Institutes of Health (MH099660)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- neonatal maternal separation, early life stress, adult hippocampal neurogenesis, neural progenitor cells, neuronal differentiation, DNA methylation, retinoic acid receptor alpha, DNMT1, decitabine, epigenetic regulation, mental illness, dentate gyrus
- MeSH terms
- Retinoic Acid Receptor alpha, Animals, Animals, Newborn, Cells, Cultured, Female, Male, Maternal Deprivation, Neurons, Promoter Regions, Genetic, Stress, Psychological, Rats, Sprague-Dawley, Receptors, Retinoic Acid, Dentate Gyrus, DNA Methylation, Epigenesis, Genetic, Rats, Neurogenesis, Neural Stem Cells
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