Whole genome sequencing on DNA from Neil1 and/or Neil2-deficient mouse hippocampus at 6 month of age

Oxidative DNA damage in the brain has been implicated in neurodegenerative diseases and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for repair of oxidative DNA base lesions. Here, we used adult mice deficient in NEIL1 and/or NEIL2 DNA glycosylases to investigate the impact of NEIL-dependent repair of oxidative DNA base lesions on cognition and behavior. Neil1-/-Neil2-/- mice displayed hyperactivity and reduced anxiety and showed improved learning ability compared to wild type or single knockout mice. Steady-state levels of oxidative DNA base lesions were comparable between genotypes and no mutator phenotype was found in Neil1-/-Neil2-/- hippocampus, suggesting that impaired canonical repair was not the cause of altered behavior. Electrophysiological analysis indicated differences between Neil1-/-Neil2-/- and wild type mice in fiber density or number of afferent fibers in stratum oriens of the hippocampal CA1 region. Within CA1, NEIL1 and NEIL2 jointly regulated transcription in genes relevant for synaptic composition and function. At protein level, we observed an altered synaptic composition, mainly affecting regulatory subunits of the NMDA-receptor. We postulate a cooperative function of NEIL1 and NEIL2 in genome regulation beyond canonical BER that modulates memory formation and anxiety.