Oxidative Stress-Induced Damage to the Developing Hippocampus Is Mediated by GSK3β

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 beta activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 beta 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.

Automated summary

Neonatal brain injury can lead to cognitive deficits due to oxidative stress. The mechanisms underlying hippocampal damage and long-term changes in memory and learning are not well understood. This study used high oxygen tension to induce oxidative stress in neonatal mice and found that it caused reactive oxygen species, cell death, and reduced interneuron maturation, inhibitory postsynaptic currents, and dentate progenitor proliferation in the hippocampus. Surprisingly, post-injury interneuron stimulation improved inhibitory activity and memory tasks, indicating reversibility. Inhibiting glycogen synthase kinase 3 beta in interneurons during oxidative stress restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, and hippocampal-dependent behavior. Targeting interneuron function biochemically may be beneficial for learning deficits caused by oxidative damage.