Cited by 113Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchStress Responses and Cortisol

Role of the Astroglial Glutamate Exchanger xCT in Ventral Hippocampus in Resilience to Stress

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Nasca, Carla, Bigio, Benedetta, Zelli, Danielle, de Angelis, Paolo, Lau, Timothy, Okamoto, Masahiro, Soya, Hideyo, Ni, Jason +5 more·2017·Neuron

Abstract

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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Crossref · 10.1016/j.neuron.2017.09.020

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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.
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
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 › 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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