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

Worldwide, 15 million children are born preterm every year. Modern medical care has largely improved the survival and outcome of very preterm babies, yet a high morbidity of preterm infants is still true and often includes impaired neurological development. Causes of brain injury in these patients imply perinatal infection/inflammation, intracranial bleeding, and hyperoxia. While term newborns undergo a natural surge of oxygen from the hypoxic in utero conditions into room air, the increase of oxygen tension occurs prematurely in preterm infant and exposes them to oxidative stress and to hyperoxia, which may interfere with development and functionality of the immature brain. Almost 50% of children born preterm show at least one behavioral disorder during their development, such as hyperactivity, attention problems, disturbed social behavior or impaired learning behavior. Apart from perturbed myelination and impaired white matter integrity being described as common underlying pathologies, the development and migration of inhibitory GABAergic interneurons can also be affected and may represent an important cause of learning disabilities and behavioral problems. In particular, development of interneurons peaks during the last trimester ofpregnancy and is considered being a very vulnerable process easily hampered by environmental changes caused by preterm birth. Accordingly, numbers of GABAergic interneurons were found to be clearly reduced in the cerebral cortex of former preterm infants in post mortem studies. In our preliminary studies in newborn mice, we could demonstrate that neonatal hyperoxia causes a reduction of cortical GABAergic interneurons, most likely through disturbed migration. In our results, Sdf1 synthesis is reduced in the cortex, astrocytes and microglia after hyperoxia, further pointing to migrational impairment because Sdf1 regulates interneuronal migration at those ages. Our results in behavioral tests moreover indicated deficits of learning behavior and social behavior after hyperoxia. To further confirm the role of impaired migration for the interneuronal and behavioral changes found in hyperoxia-experienced mice, we will apply conditional knockout of Sdf1 in astrocytes and in microglia in vivo, and compare its impact on migration and maturation of GABAergic interneurons and also on learning and social behavior at young adult ages. We moreover hypothesize that dysregulation of Hif1a (hypoxia inducible factor 1a) represents a crucial cellular mechanism causing interneuronal maldevelopment, since cellular Sdf1 expression is dependent on the activity of Hif1a, and Hif1a is downregulated by oxygen. Therefore, we will investigate Hif1a function on Sdf1 expression in astrocytes and microglia in the hyperoxia model in vitro. Altogether, the results of the proposed experiments will improve the understanding of changes in the immature brain caused by high oxygen levels, and of the behavioral deficits often found in preterm infants.

• DFG Programme: Research Grants