The inhibitory GABAergic system in the brain is involved in the etiology of various psychiatric problems, including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and others. These disorders are influenced not only by genetic but also by environmental factors, such as preterm birth, although the mechanisms underlying are not known. In a translational hyperoxia model, exposing mice pups at age P5 to 80% oxygen for 48 hours to mimic a steep rise of oxygen exposure caused by preterm birth from in utero into room air, we documented a persistent reduction of cortical mature parvalbumin expressing interneurons until adulthood. Developmental delay of cortical myelin was observed together with decreased expression of oligodendroglial glial cell-derived neurotrophic factor (GDNF), a factor being involved in interneuronal development. Electrophysiological and morphological properties of remaining interneurons were unaffected. Behavioral deficits were observed for social interaction, learning, and attention. These results elucidate that neonatal oxidative stress can lead to decreased interneuron density and to psychiatric symptoms. The obtained cortical myelin deficit and decreased oligodendroglial GDNF expression indicate an impaired oligodendroglial-interneuronal interplay contributes to interneuronal damage.

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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