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

Abstract

Myelination of axons in the neonatal brain is a highly complex process primarily achieved by oligodendroglial cells (OLs). OLs express receptors for gamma-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 (PDGFR alpha(+)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 Pdgfr alpha 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 PDGFR alpha(+)OLIG2(+) cells increased after GABA(B) receptor antagonization whereas no significant differences were visible in the Pdgfr alpha 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.