Synergistic Actions of Ogg1 and Mutyh DNA Glycosylases Modulate Anxiety-like Behavior in Mice
Monica D. Bjørge,
Gunn A. Hildrestrand,
Katja Scheffler,
Rajikala Suganthan,
Veslemøy Rolseth,
Anna Kuśnierczyk,
Alexander D. Rowe,
Cathrine B. Vågbø,
Susanne Vetlesen,
Lars Eide,
Geir Slupphaug,
Yusaku Nakabeppu,
Timothy W. Bredy,
Arne Klungland,
Magnar Bjørås
Affiliations
Monica D. Bjørge
Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
Gunn A. Hildrestrand
Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
Katja Scheffler
Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
Rajikala Suganthan
Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
Veslemøy Rolseth
Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
Anna Kuśnierczyk
Proteomics and Metabolomics Core Facility PROMEC, Norwegian University of Science and Technology, 7491 Trondheim, Norway
Alexander D. Rowe
Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
Cathrine B. Vågbø
Proteomics and Metabolomics Core Facility PROMEC, Norwegian University of Science and Technology, 7491 Trondheim, Norway
Susanne Vetlesen
Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
Lars Eide
Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
Geir Slupphaug
Proteomics and Metabolomics Core Facility PROMEC, Norwegian University of Science and Technology, 7491 Trondheim, Norway
Yusaku Nakabeppu
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, and Research Center for Nucleotide Pool, Kyushu University, Fukuoka 812-8582, Japan
Timothy W. Bredy
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Arne Klungland
Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
Magnar Bjørås
Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway
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.
