IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v6y2015i1d10.1038_ncomms7761.html
   My bibliography  Save this article

Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system

Author

Listed:
  • Paul S. Baxter

    (Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square)

  • Karen F.S. Bell

    (Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square)

  • Philip Hasel

    (Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square)

  • Angela M. Kaindl

    (Institute of Cell Biology and Neurobiology, Charité—Universitätsmedizin Berlin
    Charité—Universitätsmedizin Berlin)

  • Michael Fricker

    (University of Cambridge)

  • Derek Thomson

    (Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square)

  • Sean P. Cregan

    (The University of Western Ontario, J Allyn Taylor Centre for Cell Biology)

  • Thomas H. Gillingwater

    (Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square)

  • Giles E. Hardingham

    (Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square)

Abstract

How the brain’s antioxidant defenses adapt to changing demand is incompletely understood. Here we show that synaptic activity is coupled, via the NMDA receptor (NMDAR), to control of the glutathione antioxidant system. This tunes antioxidant capacity to reflect the elevated needs of an active neuron, guards against future increased demand and maintains redox balance in the brain. This control is mediated via a programme of gene expression changes that boosts the synthesis, recycling and utilization of glutathione, facilitating ROS detoxification and preventing Puma-dependent neuronal apoptosis. Of particular importance to the developing brain is the direct NMDAR-dependent transcriptional control of glutathione biosynthesis, disruption of which can lead to degeneration. Notably, these activity-dependent cell-autonomous mechanisms were found to cooperate with non-cell-autonomous Nrf2-driven support from astrocytes to maintain neuronal GSH levels in the face of oxidative insults. Thus, developmental NMDAR hypofunction and glutathione system deficits, separately implicated in several neurodevelopmental disorders, are mechanistically linked.

Suggested Citation

  • Paul S. Baxter & Karen F.S. Bell & Philip Hasel & Angela M. Kaindl & Michael Fricker & Derek Thomson & Sean P. Cregan & Thomas H. Gillingwater & Giles E. Hardingham, 2015. "Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7761
    DOI: 10.1038/ncomms7761
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms7761
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms7761?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7761. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.