Under normal conditions, premature infants have an underdeveloped antioxidant defense system that can prevent or delay several forms of cellular damage. These underdeveloped defense systems cannot fully defend against oxidative stress in a hyperoxia environment, causing damage to various brain regions in the absence of available treatments or preventive measures.
Based on preclinical research, experts at Children’s National Hospital have found that oxidative stress overactivates a glucose-metabolizing enzyme, GSK3β, altering the development of hippocampal interneurons and impairing learning and memory. The researchers also inhibited GSK3β in hippocampal interneurons, reversing these cellular and cognitive deficits.
“I am delighted that we have identified deficits in memory development in a specific cell population in the hippocampus,” said Dr. Vittorio Gallo, interim chief academic officer and interim director of the National Children’s Hospital and principal investigator of the Center for Intellectual and Developmental Disabilities in the District of Columbia. . “I didn’t expect that we could do this on a granular level, identifying cell populations that are sensitive to oxidative stress and their underlying signaling pathways and molecular mechanisms.”
The role of oxidative stress in the developing hippocampus, and the involvement of GSK3β in oxidative stress-induced neurodevelopmental disorders and cognitive deficits, have not been explored until now. Goldstein et al believe that this study paves the way for the field as a viable approach to maximize functional recovery after neonatal brain injury.
To better understand the mechanisms of neonatal brain injury, the researchers simulated brain injury by inducing high oxygen levels for short periods of time in preclinical models. This exploration led to unraveling the basis of cognitive deficits, including the pathophysiology of the developing hippocampus and the molecular mechanisms of oxidative damage.
Once they identified what caused the cell damage, the researchers used a gene-targeted approach to reduce GSK3β levels in POMC-expressing cells or Gad2-expressing interneurons. By modulating GSK3β levels in neurons — but not cells expressing POMC — inhibitory neurotransmission was significantly improved, and memory impairment caused by high oxygen levels was reversed.