title: Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system.
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.
authors: Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors: Paul S
authors: PS
authors: Baxter
authors: Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors: Karen F S
authors: KF
authors: Bell
authors: Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors: Philip
authors: P
authors: Hasel
authors: 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.
authors: Angela M
authors: AM
authors: Kaindl
authors: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK.
authors: Michael
authors: M
authors: Fricker
authors: Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors: Derek
authors: D
authors: Thomson
authors: Department of Physiology &Pharmacology, The University of Western Ontario, J Allyn Taylor Centre for Cell Biology, 100 Perth Drive, London, Ontario, Canada N6A 5K8.
authors: Sean P
authors: SP
authors: Cregan
authors: Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors: Thomas H
authors: TH
authors: Gillingwater
authors: Centre for Integrative Physiology, University of Edinburgh School of Biomedical Sciences, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors: Giles E
authors: GE
authors: Hardingham
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D054351:Electrical Synapses / Q000187:drug effects / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000187:drug effects / Q000378:metabolism*; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D018691:Excitatory Amino Acid Antagonists; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C488588:PUMA protein, mouse; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D025521:Tumor Suppressor Proteins; D016291:Dizocilpine Maleate; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D005978:Glutathione