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

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

doi:10.1038/ncomms7761

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

Nat Commun. 2015 Apr 9:6:6761. doi: 10.1038/ncomms7761.

Authors

Paul S Baxter¹, Karen F S Bell¹, Philip Hasel¹, Angela M Kaindl², Michael Fricker³, Derek Thomson¹, Sean P Cregan⁴, Thomas H Gillingwater¹, Giles E Hardingham¹

Affiliations

¹ Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
² 1] Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany [2] Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
³ Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK.
⁴ Department of Physiology &Pharmacology, The University of Western Ontario, J Allyn Taylor Centre for Cell Biology, 100 Perth Drive, London, Ontario, Canada N6A 5K8.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis Regulatory Proteins / genetics
Astrocytes / drug effects
Astrocytes / metabolism
Cells, Cultured
Cerebral Cortex / cytology
Dizocilpine Maleate / pharmacology
Electrical Synapses / drug effects
Electrical Synapses / metabolism*
Excitatory Amino Acid Antagonists / pharmacology
Frontal Lobe / drug effects
Frontal Lobe / metabolism*
Gene Expression Regulation
Glutathione / drug effects
Glutathione / metabolism*
Glutathione Peroxidase / drug effects
Glutathione Peroxidase / metabolism*
Glutathione Transferase / drug effects
Glutathione Transferase / metabolism*
Mice
Mice, Knockout
NF-E2-Related Factor 2 / drug effects
NF-E2-Related Factor 2 / metabolism
Neurons / drug effects
Neurons / metabolism*
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species / metabolism
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate / metabolism*
Transcription, Genetic / drug effects
Tumor Suppressor Proteins / genetics

Substances

Apoptosis Regulatory Proteins
Excitatory Amino Acid Antagonists
NF-E2-Related Factor 2
Nfe2l2 protein, rat
PUMA protein, mouse
Reactive Oxygen Species
Receptors, N-Methyl-D-Aspartate
Tumor Suppressor Proteins
Dizocilpine Maleate
Glutathione Peroxidase
Glutathione Transferase
Glutathione

Abstract

Publication types

MeSH terms

Substances

Grants and funding