Neonatal Oxidative Stress Impairs Cortical Synapse Formation and GABA Homeostasis in Parvalbumin-Expressing
Till Scheuer1, Stefanie Endesfelder1, Elena Auf dem Brinke1
1Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Neonatology, Augustenburger Platz 1, 13353 Berlin, Germany.
Insights
Neonatal brain injury from preterm birth is linked to oxidative stress. High oxygen exposure damages GABAergic interneurons, potentially explaining behavioral issues in preterm infants.
Area of Science:
- Neuroscience
- Developmental Biology
- Neonatal Research
Background:
- Neonatal brain injury is a significant complication of preterm birth.
- The immature brain is vulnerable to oxidative stress from environmental changes after birth, particularly increased oxygen exposure.
- Hyperoxia can impair neuronal development and contribute to long-term neurological deficits.
Purpose of the Study:
- To investigate the impact of neonatal hyperoxia on the maturation of cortical GABAergic interneurons.
- To determine if increased oxygen exposure induces oxidative stress and affects neuronal development in the neonatal brain.
- To explore the consequences of hyperoxia-induced oxidative stress on synaptogenesis and related signaling pathways.
Main Methods:
- Exposed 5-day-old C57BL/6 mice to hyperoxia (80% oxygen) or normoxia (21% oxygen) for 48 hours.
- Assessed oxidative stress by measuring tyrosine nitration of proteins.
- Analyzed the density and maturation of parvalbumin-expressing (PVALB) cortical interneurons using immunostaining and Western blot for glutamate decarboxylase 67 (GAD67) and gamma-aminobutyric acid (GABA).
- Evaluated synaptogenesis markers (synapsin 1, synapsin 2, synaptophysin) and PI3K signaling pathway activity.
Main Results:
- Hyperoxia induced oxidative stress, evidenced by elevated tyrosine nitration.
- Reduced density of PVALB+ cortical interneurons and impaired perineuronal net formation were observed in hyperoxic mice.
- Maturational deficits in PVALB+ interneurons included decreased GAD67 expression and lower GABA fluorescence intensity.
- Hyperoxia negatively impacted cortical synaptogenesis, decreasing expression of synapsin 1, 2, and synaptophysin.
- Developmental delay in synaptic marker expression and reduced PI3K signaling were associated with hyperoxia.
Conclusions:
- Neonatal exposure to increased oxygen levels causes oxidative stress in the immature brain.
- This oxidative stress leads to damage and maturational deficits in cortical GABAergic interneurons.
- Impaired interneuron development and synaptogenesis may underlie the high incidence of psychiatric and behavioral alterations observed in preterm infants.
Abstract:
Neonatal brain injury is often caused by preterm birth. Brain development is vulnerable to increased environmental stress, including oxidative stress challenges. Due to a premature change of the fetal living environment from low oxygen in utero into postnatal high-oxygen room air conditions ex utero, the immature preterm brain is exposed to a relative hyperoxia, which can induce oxidative stress and impair neuronal cell development. To simulate the drastic increase of oxygen exposure in the immature brain, 5-day-old C57BL/6 mice were exposed to hyperoxia (80% oxygen) for 48 hours or kept in room air (normoxia, 21% oxygen) and mice were analyzed for maturational alterations of cortical GABAergic interneurons. As a result, oxidative stress was indicated by elevated tyrosine nitration of proteins. We found perturbation of perineuronal net formation in line with decreased density of parvalbumin-expressing (PVALB) cortical interneurons in hyperoxic mice. Moreover, maturational deficits of cortical PVALB+ interneurons were obtained by decreased glutamate decarboxylase 67 (GAD67) protein expression in Western blot analysis and lower gamma-aminobutyric acid (GABA) fluorescence intensity in immunostaining. Hyperoxia-induced oxidative stress affected cortical synaptogenesis by decreasing synapsin 1, synapsin 2, and synaptophysin expression. Developmental delay of synaptic marker expression was demonstrated together with decreased PI3K-signaling as a pathway being involved in synaptogenesis. These results elucidate that neonatal oxidative stress caused by increased oxygen exposure can lead to GABAergic interneuron damage which may serve as an explanation for the high incidence of psychiatric and behavioral alterations found in preterm infants.
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