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Role of the Astroglial Glutamate Exchanger xCT in Ventral Hippocampus in Resilience to Stress
Open accessAbstract
We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and identify a role for the astroglial xCT in ventral dentate gyrus (vDG) in stress and antidepressant responses. We provide an RNA-seq roadmap for the stress-sensitive vDG. The transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27ac to regulate expression of xCT, which is also reduced in a genetic mouse model of inherent susceptibility to depressive-like behavior. Pharmacologically, modulating histone acetylation with acetyl-L-carnitine (LAC) or acetyl-N-cysteine (NAC) rapidly increases xCT and activates a network with mGlu2 receptors to prime an enhanced glutamate homeostasis that promotes both pro-resilient and antidepressant-like responses. Pharmacological xCT blockage counteracts NAC prophylactic effects. GFAP+-Cre-dependent overexpression of xCT in vDG mimics pharmacological actions in promoting resilience. This work establishes a mechanism by which vDG protection leads to stress resilience and antidepressant responses via epigenetic programming of an xCT-mGlu2 network.
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“We should briefly note that the stratification approach that we have followed is in line with an emerging trend in the literature, taking into account individual differences in behavioral outcomes when examining underlying neurobiology36,39–44.”
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Metadata
- Authors
- Nasca, C., Bigio, B., Zelli, D., de Angelis, P., Lau, T., Okamoto, M., Soya, H., Ni, J., Brichta, L., Greengard, P., Neve, R. L., Lee, F. S., & McEwen, B. S.
- Affiliations
- Rockefeller University (US)
- University of Tsukuba (JP)
- Massachusetts General Hospital (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Nasca, Carla
- McEwen, Bruce S.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 96
- Issue
- 2
- Pages
- 402-413.e5
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2762868429
- Cited by
- 113
- References
- 60
- Citations by year
- 2026: 1 · 2025: 12 · 2024: 6 · 2023: 10 · 2022: 15 · 2021: 20 · 2020: 16 · 2019: 17 · 2018: 14 · 2017: 2
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AFSP
- (American Foundation for Suicide Prevention)
- HDRF (Hope for Depression Research Foundation; RGA# DTF Phase II (D))
- NIH (R01 MH41256)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- astrocytes, ventral dentate gyrus, ventral hippocampus, stress resilience, antidepressant response, glutamate homeostasis, REST transcription factor, H3K27ac, histone acetylation, acetyl-L-carnitine, mGlu2 receptor, depression-like behavior, RNA-seq
- MeSH terms
- Animals, Astrocytes, Depression, Hippocampus, Male, Mice, Inbred C57BL, Mice, Transgenic, Random Allocation, Stress, Psychological, Receptors, Metabotropic Glutamate, Glutamic Acid, Amino Acid Transport System y+, Mice
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