Neuronal activity induces glutathione metabolism gene expression in astrocytes

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.