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.
Highlights
Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline
General activity levels were examined in an open field maze (OFM) and anxiety was monitored by using an elevated zero maze (EZM)
Across stratum pyramidale (SP), we found significantly reduced NR2A-reactivity in Neil2−/− and Neil1−/−Neil2−/− mice compared to WT (Supplementary Fig. 6a)
Summary
Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. Previous studies of mice lacking NEIL1 revealed a metabolic phenotype with variable penetrance, impaired memory retention and defects in olfactory function, as well as increased sensitivity to ischemic brain injury[23,30,31,32]. We used mice deficient in NEIL1 and/or NEIL2 DNA glycosylases to elucidate the roles of these enzymes in behavior and cognition (i.e., activity, anxiety, learning, and memory) and to study their impact on genome stability, gene expression and electrophysiological features in the hippocampus. Our study revealed an altered behavioral phenotype in NEIL1/ NEIL2-deficient mice, which was accompanied by differential regulation of genes relevant for synaptic function and instability of NMDA-receptor architecture in the hippocampus. No accumulation of DNA damage or mutations point to a NEIL1/NEIL2dependent regulation of synaptic factors that is not explained by the enzymes’ function in DNA repair but rather a noncanonical contribution to gene regulation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
