Synergistic Actions of Ogg1 and Mutyh DNA Glycosylases Modulate Anxiety-like Behavior in Mice

Ogg1 and Mutyh DNA glycosylases cooperate to prevent mutations caused by 8-oxoG, a major premutagenic DNA lesion associated with cognitive decline. We have examined behavior and cognitive function in mice deficient of these glycosylases. Ogg1^−/−Mutyh^−/− mice were more active and less anxious, with impaired learning ability. In contrast, Mutyh^−/− mice showed moderately improved memory. We observed no apparent change in genomic 8-oxoG levels, suggesting that Ogg1 and Mutyh play minor roles in global repair in adult brain. Notably, transcriptome analysis of hippocampus revealed that differentially expressed genes in the mutants belong to pathways known to be involved in anxiety and cognition. Esr1 targets were upregulated, suggesting a role of Ogg1 and Mutyh in repression of Esr1 signaling. Thus, beyond their involvement in DNA repair, Ogg1 and Mutyh regulate hippocampal gene expression related to cognition and behavior, suggesting a role for the glycosylases in regulating adaptive behavior. Ogg1 and Mutyh cooperate to prevent mutations caused by 8-oxoG. Bjørge et al. report increased activity, decreased anxiety, and impaired learning in Ogg1^−/−Mutyh^−/− mice but unaltered 8-oxoG levels. Genes involved in anxiety and cognition are differentially expressed in Ogg1^−/−Mutyh^−/− mice, suggesting Ogg1 and Mutyh modulate gene expression related to adaptive behavior.