Postnatal myelination of the immature rat cingulum is regulated by GABAB receptor activity.

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 GABAA and GABAB in the neonatal rat brain. Daily injections of the reverse GABAA receptor agonist (DMCM) and the GABAB 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 GABAB 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 GABAB receptor activity as a potential modulator of oligodendroglial development.

Reduction of cortical parvalbumin-expressing GABAergic interneurons in a rodent hyperoxia model of preterm birth brain injury with deficits in social behavior and cognition.

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 underlying mechanisms are not known. In a translational hyperoxia model, exposing mice pups at P5 to 80% oxygen for 48 h 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 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 demonstrate 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 that an impaired oligodendroglial-interneuronal interplay contributes to interneuronal damage.