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Neuronal activity induces glutathione metabolism gene expression in astrocytes.

ABSTRACT: The idea that astrocytes provide support for neurons has a long history, but whether neurons play an instructive role in these processes is poorly understood. To address this question, we co-culture astrocytes with genetically labeled neurons, permitting their separation by flow cytometry, and test whether the presence of neurons influences the astrocyte transcriptome. We find that numerous pathways are regulated in the co-cultured astrocytes, in a time-dependent matter coincident with synaptic maturation. In particular, the induction of glutathione metabolic genes is prominent, resulting in increased glutathione production. We show that the induction of the glutathione pathway is mediated by astrocytic metabotropic glutamate receptors. Using a candidate approach, we identify direct binding of the nuclear factor E2-related factor, NRF2, to several of the induced genes. Blocking nuclear accumulation of astrocytic NRF2 abolishes neuron-induced glutathione gene induction and glutathione production. Our results suggest that astrocyte transcriptional and metabolic profiles are tightly coupled to the activity of neurons, consistent with the model that astrocytes dynamically support healthy brain function.

SUBMITTER: McGann JC

PROVIDER: S-EPMC6185788 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Neuronal activity induces glutathione metabolism gene expression in astrocytes.

McGann James C JC Mandel Gail G

Glia 20180725 9

The idea that astrocytes provide support for neurons has a long history, but whether neurons play an instructive role in these processes is poorly understood. To address this question, we co-culture astrocytes with genetically labeled neurons, permitting their separation by flow cytometry, and test whether the presence of neurons influences the astrocyte transcriptome. We find that numerous pathways are regulated in the co-cultured astrocytes, in a time-dependent matter coincident with synaptic ...[more]

PMID: 30043519

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Project description:The metabolism and intercellular transfer of glutathione or its precursors may play an important role in cellular defense against oxidative stress, a common hallmark of neurodegeneration. In the 1990s, several studies in the Neurobiology field led to the widely accepted notion that astrocytes produce large amounts of glutathione that serve to feed neurons with precursors for glutathione synthesis. This assumption has important implications for health and disease since a reduction in this supply from astrocytes could compromise the capacity of neurons to cope with oxidative stress. However, at first glance, this shuttling would imply a large energy expenditure to get to the same point in a nearby cell. Thus, are there additional underlying reasons for this expensive mechanism? Are neurons unable to import and/or synthesize the three non-essential amino acids that are the glutathione building blocks? The rather oxidizing extracellular environment favors the presence of cysteine (Cys) as cystine (Cis), less favorable for neuronal import. Therefore, it has also been proposed that astrocytic GSH efflux could induce a change in the redox status of the extracellular space nearby the neurons, locally lowering the Cis/Cys ratio. This astrocytic glutathione release would also increase their demand for precursors, stimulating Cis uptake, which these cells can import, further impacting the local decline of the Cis/Cys ratio, in turn, contributing to a more reduced extracellular environment and subsequently favoring neuronal Cys import. Here, we revisit the experimental evidence that led to the accepted hypothesis of astrocytes acting as suppliers of neuronal glutathione precursors, considering recent data from the Human Protein Atlas. In addition, we highlight some potential drawbacks of this hypothesis, mainly supported by heterogeneous cellular models. Finally, we outline additional and more cost-efficient possibilities by which astrocytes could support neuronal glutathione levels, including its shuttling in extracellular vesicles.

Dataset Information

Neuronal activity induces glutathione metabolism gene expression in astrocytes.

Publications

Neuronal activity induces glutathione metabolism gene expression in astrocytes.

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