NEIL1 and NEIL2 DNA glycosylases modulate anxiety and learning in a cooperative manner in mice

Gunn A Hildrestrand; Veslemøy Rolseth; Nicolas Kunath; Rajikala Suganthan; Vidar Jensen; Anna M Bugaj; Marion S Fernandez-Berrocal; Sunniva B Sikko; Susanne Vetlesen; Anna Kuśnierczyk; Ann-Karin Olsen; Kristine B Gützkow; Alexander D Rowe; Wei Wang; Olve Moldestad; Monica D Syrstad; Geir Slupphaug; Lars Eide; Arne Klungland; Pål Sætrom; Luisa Luna; Jing Ye; Katja Scheffler; Magnar Bjørås

doi:10.1038/s42003-021-02864-x

NEIL1 and NEIL2 DNA glycosylases modulate anxiety and learning in a cooperative manner in mice

Commun Biol. 2021 Dec 2;4(1):1354. doi: 10.1038/s42003-021-02864-x.

Authors

Gunn A Hildrestrand^#¹, Veslemøy Rolseth^#^{1

2}, Nicolas Kunath^#³, Rajikala Suganthan¹, Vidar Jensen⁴, Anna M Bugaj³, Marion S Fernandez-Berrocal³, Sunniva B Sikko³, Susanne Vetlesen¹, Anna Kuśnierczyk⁵, Ann-Karin Olsen^{6

7}, Kristine B Gützkow^{6

7}, Alexander D Rowe^{1

8}, Wei Wang³, Olve Moldestad^{9

10}, Monica D Syrstad¹, Geir Slupphaug⁵, Lars Eide¹¹, Arne Klungland^{1

12}, Pål Sætrom³, Luisa Luna¹, Jing Ye³, Katja Scheffler^{3

13

14}, Magnar Bjørås^{15

16}

Affiliations

¹ Department of Microbiology, Oslo University Hospital and University of Oslo, N-0424, Oslo, Norway.
² Department of Forensic Sciences, Division of Laboratory Medicine, Oslo University Hospital, N-0424, Oslo, Norway.
³ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, N-7491, Trondheim, Norway.
⁴ GliaLab, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317, Oslo, Norway.
⁵ Proteomics and Modomics Experimental Core Facility (PROMEC), Norwegian University of Science and Technology, N-7491, Trondheim, Norway.
⁶ Department of Molecular Biology, National Institute of Public Health, N-0456, Oslo, Norway.
⁷ Centre of Excellence "Centre for Environmental Radiation" (CERAD), NMBU, N-1433, Ås, Norway.
⁸ Department of Newborn Screening, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, N-0424, Oslo, Norway.
⁹ Laboratory of Cellular Neurophysiology and Ion Channel Function, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317, Oslo, Norway.
¹⁰ Department for Rare Disorders, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, N-0424, Oslo, Norway.
¹¹ Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, N-0424, Oslo, Norway.
¹² Department of Biosciences, University of Oslo, N-0371, Oslo, Norway.
¹³ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, N-7491, Trondheim, Norway.
¹⁴ Department of Neurology, University Hospital of Trondheim, N-7006, Trondheim, Norway.
¹⁵ Department of Microbiology, Oslo University Hospital and University of Oslo, N-0424, Oslo, Norway. magnar.bjoras@ntnu.no.
¹⁶ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, N-7491, Trondheim, Norway. magnar.bjoras@ntnu.no.

^# Contributed equally.

Abstract

Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases affect cognition in mice, while the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in knockout mouse models. Neil1^-/-Neil2^-/- mice display hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels are comparable between genotypes and no mutator phenotype is found. Thus, impaired canonical repair is not likely to explain the altered behavior. Electrophysiology suggests reduced axonal activation in the hippocampal CA1 region in Neil1^-/-Neil2^-/- mice and lack of NEIL1 and NEIL2 causes dysregulation of genes in CA1 relevant for synaptic function. We postulate a cooperative function of NEIL1 and NEIL2 in genome regulation, beyond canonical BER, modulating behavior in mice.

Publication types

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

MeSH terms

Animals
Anxiety / genetics*
DNA Glycosylases / genetics*
DNA Glycosylases / metabolism
Gene Expression Regulation
Hippocampus / physiology
Learning*
Male
Mice / genetics
Mice / psychology*
Mice, Knockout
Oxidative Stress / physiology

Substances

DNA Glycosylases
Neil1 protein, mouse
Neil2 protein, mouse