Impact of oxidative DNA damage repair on brain function

Base excision repair (BER) is the primary pathway for repair of oxidative DNA damage caused by various agents including reactive oxygen species. BER is initiated by DNA glycosylases that recognize and remove damaged DNA bases, and the function of the glycosylases OGG1, MUTYH, NEIL1, and NEIL2 are the main focus of this thesis. DNA glycosylases have been suggested to be involved in prevention of neuronal cell death under cerebral hypoxia-ischemia (HI), but the mechanism of neuroprotection is yet to be determined. In the first part of the study, we investigated the role of OGG1, MUTYH, NEIL1, and NEIL2 following HI in newborn mice. We demonstrated that MUTYH- and NEIL1-deficient mice were more sensitive to HI in most regions of the brain, whereas mice lacking OGG1 showed increased sensitivity mostly in the hippocampal area. Removal of NEIL2, on the other hand, led to neuroprotection. We did not discover major discrepancies in quantification of DNA damage in any of the genotypes. RNA sequencing revealed a dysregulation of the inflammatory response in the various knockouts, and increased IL-1β expressed in activated microglia in the hippocampus (HC) of OGG1- and MUTYH-deficient mice. It thus appears that MUTYH has a neuroprotective function, while NEIL2 seems to play a detrimental role in the brain following a HI insult. Accumulation of oxidative DNA damage is associated with aging and cognitive decline. In the second part of the study, we focused on the function of the OGG1 and MUTYH DNA glycosylases in learning and memory in adult animals. The OGG1/MUTYH double knockout mice were more active and less anxious than wild type mice and both the double knockout and the OGG1 knockout mice displayed impaired learning. We observed no significant differences in DNA damage accumulation between the genotypes. RNA sequencing revealed candidate genes and pathways in anxiety and cognitive functions. Thus, the investigated DNA glycosylases seem to adopt distinct roles in regulation of behavior and cognitive function