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We thank Deighton et al. (1) for highlighting the importance of antioxidant pathway regulation in the brain, the topic of our recent study (2). In their letter, Deighton et al. show that expression of antioxidant genes Srxn1 and xCT [which can be regulated by nuclear factor erythroid 2-related factor 2 (Nrf2)] is increased by neuronal activity in cortical cultures that lack both Nrf2 and astrocytes (1). Although this finding is in agreement with their previous work, which showed that activity regulates neuronal Srxn1 expression through transcription factors ATF4 and AP-1, the authors raised a possibility that activity-induced increase in Gclc and Nqo1 expression in mixed hippocampal cultures (2) was also Nrf2- and astrocyte-independent. However, in contrast to Srxn1, xCT, and other genes that are regulated by multiple transcription factors, Nqo1 gene expression is controlled exclusively through Nrf2/antioxidant response element (ARE) interaction (3) [a possible regulation by AP-2 was reported in 1996 (4), but has not been confirmed since]. …

Reply to Deighton et al.: Neuronal activity regulates distinct antioxidant pathways in neurons and astrocytes