Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents, and dentate progenitor proliferation. Postinjury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and somatostatin, HO aberrantly activated glycogen synthase kinase 3 β activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 β during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage.

SIGNIFICANCE STATEMENT Premature infants are especially vulnerable to oxidative stress, as their antioxidant defenses are underdeveloped. Indeed, high oxygen tension is associated with poor neurologic outcomes. Because of its sustained postnatal development and role in learning and memory, the hippocampus is especially vulnerable to oxidative damage in premature infants. However, the role of oxidative stress in the developing hippocampus has yet to be explored. With ever-rising rates of neonatal brain injury and no universally viable approach to maximize functional recovery, a better understanding of the mechanisms underlying neonatal brain injury is needed. Addressing this need, this study uses perinatal hyperoxia to study cognitive deficits, pathophysiology, and molecular mechanisms of oxidative damage in the developing hippocampus.

新生儿脑损伤使发育中的大脑容易受到氧化应激的影响，导致认知缺陷。然而，氧化应激引起的海马回路损伤以及记忆和学习长期变化的机制尚不清楚。我们在两性新生小鼠中使用高氧张力或高氧 (H2O) 来研究氧化应激在海马损伤中的作用。围产期 H2O 诱导活性氧和细胞死亡，同时减少中间神经元成熟、抑制突触后电流和齿状祖细胞增殖。受伤后中间神经元刺激令人惊讶地改善了抑制活动和记忆任务，表明可逆性。随着 Wnt 信号成分和生长抑素的海马水平降低，H2O 异常激活糖原合酶激酶 3 β 活性。在 H2O 攻击期间，中间神经元糖原合酶激酶 3 β 的药理学抑制或消融恢复了祖细胞增殖、中间神经元发育、抑制/兴奋平衡以及海马依赖性行为。中间神经元功能的生化靶向可能有益于氧化损伤引起的学习缺陷。

重要性声明早产儿特别容易受到氧化应激的影响，因为他们的抗氧化防御能力不发达。事实上，高氧压与不良的神经系统结局有关。由于其持续的产后发育和在学习和记忆中的作用，海马体特别容易受到早产儿的氧化损伤。然而，氧化应激在发育中的海马体中的作用还有待探索。随着新生儿脑损伤率的不断上升，并且没有普遍可行的方法来最大限度地恢复功能，需要更好地了解新生儿脑损伤的机制。针对这一需求，本研究使用围产期高氧来研究发育中的海马体中的认知缺陷、病理生理学和氧化损伤的分子机制。