Thousands of infants are born each year with signs of brain injury caused by a lack of adequate blood flow and oxygen delivery. The findings of a new preclinical study by researchers from Children’s National Hospital may pave the way toward better understanding, prevention, and recovery of neonatal brain injuries.

The findings are published in the Journal of Neuroscience in a paper titled, “Oxidative stress-induced damage to the developing hippocampus is mediated by GSK3beta.”

In the study, the researchers from Children’s National Hospital, found that oxidative stress over activates a glucose metabolism enzyme, GSK3β, altering hippocampal interneuron development, and impairing learning and memory.

“Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit,” wrote the researchers. “However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood.”

The researchers used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage.

“I am thrilled that we identified a defect in a specific cell population in the hippocampus for memory development,” said Vittorio Gallo, PhD, interim chief academic officer and interim director of the Children’s National Research Institute, and principal investigator for the District of Columbia Intellectual and Developmental Disabilities Research Center. “I did not think we would be able to do it at a refined level, identifying cell populations sensitive to oxidative stress and its underlying signaling pathway and molecular mechanism.”

The researchers mimicked the brain injury by inducing high oxygen levels in a preclinical model for a short time. Doing this, revealed the underpinnings of the cognitive deficits, including molecular mechanisms of oxidative damage in the developing hippocampus.

They used a gene-targeted approach to reduce GSK3β levels in POMC-expressing cells or Gad2-expressing interneurons once they discovered what caused oxidative damage. By regulating the levels of GSK3β in interneurons⁠—but not in POMC-expressing cells—inhibitory neurotransmission was significantly improved and memory deficits due to high oxygen levels were reversed.

“Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage,” concluded the researchers.