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.

Myelination of axons in the neonatal brain is a highly complex process primarily achieved by oligodendroglial cells (OLs). OLs express receptors for γ-aminobutyric acid (GABA) which is released from cortical interneurons on a basal level, while glial cells can be a source of GABA, too. We investigated GABA-induced oligodendroglial maturation, proliferation, apoptosis, and myelin production after pharmacological inhibition of GABA A and GABA B in the neonatal rat brain. Daily injections of the reverse GABA A receptor agonist (DMCM) and the GABA B receptor antagonist (CGP35348) were performed from postnatal day 6 (P6) to P11. MBP expression was examined by Western blots and immunohistochemistry. Furthermore, we determined the number of CC1 + OLIG2 + and CNP + OLIG2 + cells to assess maturation, the number of PCNA + OLIG2 + oligodendrocytes to assess proliferation, the number of oligodendrocyte precursor cells (PDGFRα + OLIG2 + ), and apoptosis of OLs (CASP3A + OLIG2 + ) as well as apoptotic cells in total (CASP3A + DAPI + ) at P11 and P15. In addition, we analyzed the expression Pdgfrα and CNP. MBP expression was significantly reduced after CGP treatment at P15. In the same animal group, CNP expression and CNP + OLIG2 + cells decreased temporarily at P11. At P15, the proliferation of PCNA + OLIG2 + cells and the number of PDGFRα + OLIG2 + cells increased after GABA B receptor antagonization whereas no significant differences were visible in the Pdgfrα gene expression. No changes in apoptotic cell death were observed. CGP treatment induced a transient maturational delay at P11 and deficits in myelin expression at P15 with increased oligodendroglial proliferation. Our in vivo study indicates GABA B receptor activity as a potential modulator of oligodendroglial development.

No abstract