Author: 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.
Description: 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.
Subject headings: Amino Acid Transport System y+/physiology; Animals; Astrocytes/physiology; Depression/genetics/metabolism/psychology; Glutamic Acid/metabolism; Hippocampus/physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Random Allocation; Receptors, Metabotropic Glutamate/genetics/metabolism; Stress, Psychological/genetics/metabolism/psychology; acetylcarnitine; antidepressant; dentate gyrus; epigenetics; glutamate homeostasis; hippocampus; histone; mGlu2; resilience; stress
Publication year: 2017
Journal or book title: Neuron
Volume: 96
Issue: 2
Pages: 402-413.e5
Find the full text :Â https://www.sciencedirect.com/science/article/pii/S0896627317308607
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Type: Journal Article
Serial number: 2021