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

doi:10.1016/j.celrep.2015.12.001

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

Cell Rep. 2015 Dec 29;13(12):2671-8. doi: 10.1016/j.celrep.2015.12.001. Epub 2015 Dec 17.

Authors

Affiliations

¹ Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
² Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
³ Proteomics and Metabolomics Core Facility PROMEC, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
⁴ Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
⁵ Proteomics and Metabolomics Core Facility PROMEC, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
⁶ 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.
⁷ Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
⁸ Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway. Electronic address: magnar.bjoras@rr-research.no.

PMID: 26711335
DOI: 10.1016/j.celrep.2015.12.001

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anxiety / enzymology*
Anxiety / genetics
Anxiety / metabolism
DNA Glycosylases / deficiency
DNA Glycosylases / genetics
DNA Glycosylases / metabolism*
Disease Models, Animal
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Reactive Oxygen Species / metabolism

Substances

Reactive Oxygen Species
DNA Glycosylases
Ogg1 protein, mouse
mutY adenine glycosylase