Endonuclease VIII-like 1 deficiency impairs survival of newly generated hippocampal neurons and memory performance in young-adult male mice.

ABSTRACT

AIMS: Efficient memory formation in rodents depends on adult neurogenesis in the subgranular zone of the hippocampus, and mounting evidence suggests that deficiencies in initiating repair of oxidatively induced DNA damage may impair neurogenesis. Hence, we aimed to determine whether loss of the DNA glycosylase, endonuclease VIII-like 1 (Neil1), affects hippocampal neurogenesis and memory performance in young-adult mice. MAIN METHODS: Eight-week-old male wild-type and Neil1-deficient (Neil1-/-) mice were treated with bromodeoxyuridine to track neuronal proliferation and differentiation. A neurosphere formation assay was further used to measure neuroprogenitor proliferative capacity. Hippocampus-related memory functions were assessed with Y-maze spontaneous alternation and novel object recognition tests. KEY FINDINGS: Young-adult male Neil1-/- mice exhibited diminished adult hippocampal neurogenesis in the dentate gyrus, probably as a result of poor survival of newly proliferated neurons. Furthermore, the Y-maze spontaneous alternation and novel object recognition tests respectively revealed that Neil1 deficiency impairs spatial and non-spatial hippocampus-related memory functions. We also found that expression of p53, a central regulator of apoptosis, was upregulated in the dentate gyrus of Neil1-/- mice, while the level of ß-catenin, a key cell survival molecule, was downregulated. SIGNIFICANCE: The DNA glycosylase, Neil1, promotes successful hippocampal neurogenesis and learning and memory in young-adult mice.