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Neuron. 2017 Oct 11;96(2):402-413.e5. doi: 10.1016/j.neuron.2017.09.020.

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

Author information

1
Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA. Electronic address: cnasca@rockefeller.edu.
2
Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA.
3
Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA; Laboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Ibaraki 305-8574, Japan.
4
Department of Sports Neuroscience, Advanced Research Initiative for Human High Performance (ARIHHP), Faculty of Health and Sport Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305-8574, Japan; Laboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Ibaraki 305-8574, Japan.
5
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
6
Gene Delivery Technology Core, Massachusetts General Hospital, 65 Landsdowne Street, Cambridge, MA 02139, USA.
7
Sackler Institute for Developmental Psychobiology, Department of Psychiatry, Weill Cornell Medical College, New York, NY 10065, USA.
8
Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA. Electronic address: mcewen@rockefeller.edu.

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.

KEYWORDS:

acetylcarnitine; antidepressant; dentate gyrus; epigenetics; glutamate homeostasis; hippocampus; histone; mGlu2; resilience; stress

PMID:
29024663
DOI:
10.1016/j.neuron.2017.09.020
[Indexed for MEDLINE]
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