
NATURE . COM {
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Title:
Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system | Nature Communications
Description:
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. How the brain’s antioxidant defenses adapt to changing demand is not well understood. Here the authors demonstrate that synaptic activity is coupled to transcriptional control of the glutathione antioxidant system via NMDA receptors, enabling neurons to tune their antioxidant defenses.
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Keywords {🔍}
gsh, activity, neurons, article, fig, synaptic, google, scholar, nmdar, cas, glutathione, neuronal, levels, system, assay, bso, expression, cultures, brain, gcl, control, oxidative, gclc, supplementary, depletion, treated, deficits, death, antioxidant, astrocytes, biosynthesis, cell, measured, min, induced, treatment, active, found, cortical, nmda, increased, redox, mcb, puma, effects, gcee, nature, receptor, hypoactivity, wafph,
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nature portfolio privacy policy extrasynaptic n-methyl-d-aspartate receptors advertising n-methyl-d-aspartate receptors prevents bic/4-ap-induced bursting nature german research foundation scientific procedures social media bic/4-ap-induced burst activity bic/4-ap-induced synaptic activity cell-autonomous nrf2-driven support astrocyte-mediated cddotfea-induced protection n-methyl-d-aspartate 0/ reprints activity-dependent cell-autonomous mechanisms kodak x-omat film exhibit activity-dependent protection γ-glutamylcysteine-ethyl ester fluoro-jade staining-based analysis transcription inhibitor actinomycin peroxynitrite-induced oxidative stress nrf2-mediated gene expression early-life oxidative stress bic-induced burst activity long-lasting neurobehavioral deficits38 oxidative stress-related biomarkers bic-induced synaptic activity observe activity-dependent neuroprotection cell type-specific distribution astrocytic nrf2-mediated neuroprotection34 synaptic activity-dependent induction author information authors gs-bimane fluorescence induced prevent activity-dependent protection observe activity-dependent protection cortical parvalbumin-positive interneurons glutamate-cysteine ligase activity research bic-induced elevated activity neurons expressing grx1-rogfp2 forming fluorescent gs-bimane colorimetric extract-based assay resting-state functional connectivity h2o2-induced neuronal death long-lasting behavioural disturbances conventional extract-based assay bic-induced ca2+ levels cellular gs-bimane signal
Questions {❓}
- N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia?
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headline:Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system
description:How the brainâs 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. How the brainâs antioxidant defenses adapt to changing demand is not well understood. Here the authors demonstrate that synaptic activity is coupled to transcriptional control of the glutathione antioxidant system via NMDA receptors, enabling neurons to tune their antioxidant defenses.
datePublished:2015-04-09T00:00:00Z
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Ion channels
Neurodevelopmental disorders
Neurotransmitters
Transcription
Science
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multidisciplinary
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headline:Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system
description:How the brainâs 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. How the brainâs antioxidant defenses adapt to changing demand is not well understood. Here the authors demonstrate that synaptic activity is coupled to transcriptional control of the glutathione antioxidant system via NMDA receptors, enabling neurons to tune their antioxidant defenses.
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Ion channels
Neurodevelopmental disorders
Neurotransmitters
Transcription
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