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Oxygen induced impairment of immature interneurons causes behavioral deficits in very preterm infants

Applicant Dr. Till Scheuer
Subject Area Pediatric and Adolescent Medicine
Term from 2019 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 419338280
 
Final Report Year 2024

Final Report Abstract

Preterm birth can result in functional and structural alterations in brain development. These developmental impairments can influence cognition and social behavior in later life. Directly after human birth, arterial oxygen tension increases dramatically. The physiological increase of oxygen availability can harm the immature organs of preterm infants. In our preterm birth hyperoxia injury model, which mimics the increase of oxygen tension, we could confirm white matter damage in cortical areas as well as detect impaired development of cortical parvalbumin expressing (PVALB+) GABAergic interneurons. Exposure to hyperoxia resulted in a permanent reduction of cortical PVALB+ interneurons. Remaining interneurons showed altered structural and functional maturation. Formation of perineuronal nets was decreased. In young adult mice, PVALB+ interneurons showed decreased GABA production. However, electrophysiological properties of cortical PVALB+ interneurons were not affected. Moreover, cortical synaptogenesis was affected by exposure to hyperoxia. Synaptic marker expression, primarily expressed by PVALB+ interneurons, was decreased in cortical samples. Cellular impairment was confirmed by behavior analyses. Hyperoxia exposed mice showed deficits in learning, attention, and cognition, as well as alterations in social behavior. Behavioral alterations, which are often seen in preterm infants. Oxygen damages the immature brain in different ways. Hyperoxia induces oxidative stress (OS), which was confirmed by increased cortical lipid peroxidation and increased cortical nitrotyrosine levels in our study. OS can specifically damage cells and tissue. In particular, immature cells and precursor cells are vulnerable to oxidative stress. Developmental processes such as myelination and oligodendrocyte precursor cell development, interneuron development, PNN formation and synaptogenesis occur interactively in the immature cortex. In our model of preterm birth brain injury, OS induces white matter damage and cortical interneuron loss. Additionally, we identified decreased oligodendroglial GDNF expression as a consequence of postnatal hyperoxia. GDNF function is involved in the migration, differentiation and maturation of MGE-derived cortical GABAergic interneurons. Furthermore, we could show the expression of the GDNF receptor in PVALB+ interneurons. Hence, the loss of the cortical PVALB+ interneurons in our study may occur in close relation to oligodendroglial damage in hyperoxic mice, which is mediated or increased by reduction of oligodendroglial GDNF. Moreover, this study supports the hypothesis of preterm birth-induced OS, which can cause impaired interneuron development. OS-induced brain injury contributes to the clinical phenotype commonly found in preterm infants. Prevention of OS in GABAergic interneurons could therefore serve as a target for neuroprotective strategies. Unfortunately, the generation of the Sdf1 knockout in astrocytes and microglia was not possible because of unpredictable problems in breeding and housing of the animals.

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