NEIL1 stimulates neurogenesis and suppresses neuroinflammation after stress

Adult neurogenesis, found in two neurogenic regions of the brain, has profound roles in neural plasticity and brain function. A hallmark feature of neurodegeneration is neuroinflammation, which can either enhance or inhibit neurogenesis depending on the context of the brain microenvironment. The consequences of deficient DNA repair in adult neurogenesis and neuroinflammation are poorly understood despite their potential relevance for homeostasis. We previously reported that loss of NEIL1, an important DNA glycosylase involved in DNA base excision repair, is associated with deficiencies in spatial memory, olfaction, and protection against ischemic stroke in mice. Here, we show that Neil1-/- mice display an anxiety-mediated behavior in the open field test, a deficient recognitive memory in novel object recognition and increased neuroinflammatory response under basal conditions. Further, mice lacking NEIL1 have decreased neurogenesis and deficient resolution of neuroinflammation following gamma irradiation (IR)-induced stress compared to WT mice. Neil1-/- IR-exposed mice also exhibit increased DNA damage and apoptosis in the hippocampus. Interestingly, behavioral tests two weeks after IR showed impaired stress response in the Neil1-/- mice. Our data indicate that NEIL1 plays an important role in adult neurogenesis and in the resolution of neuroinflammation. NEIL1 knockout (KO) and wildtype (WT) mice were placed in a stereotaxic cube box in a Nordion Gammacell 40 Exactor Irradiator, and was either subjected to whole body gamma irradiation (6 Gy) delivered at a rate of 0.74 Gy/min (irradiated) or no radiation (sham) on Day 0. After exposure, mice were returned to home cages, and cerebral cortex obtained for RNA extraction from four mice from each of the four experimental groups 20 hours after IR or sham-treatment.