Projects per year
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.
Original language | English |
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Article number | 6761 |
Journal | Nature Communications |
Volume | 6 |
DOIs | |
Publication status | Published - 9 Apr 2015 |
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Dive into the research topics of 'Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system'. Together they form a unique fingerprint.Projects
- 1 Finished
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Investigation into the differential capacity of NR2A and NR2B
Hardingham, G. (Principal Investigator) & Wyllie, D. (Co-investigator)
1/10/09 → 30/09/12
Project: Research
Profiles
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Tom Gillingwater
- Deanery of Biomedical Sciences - Chair of Anatomy
- Centre for Discovery Brain Sciences
- Euan MacDonald Centre for Motor Neuron Disease Research
- Edinburgh Neuroscience
Person: Academic: Research Active
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Giles Hardingham
- Deanery of Biomedical Sciences - City of Edinburgh Chair of Pharmacology
- Centre for Discovery Brain Sciences
- Euan MacDonald Centre for Motor Neuron Disease Research
- Edinburgh Neuroscience
- Edinburgh Imaging
Person: Academic: Research Active