Postnatal myelination of the immature rat cingulum is regulated by GABA_B 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 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.

GABAB receptor agonist baclofen promotes central nervous system remyelination

“…Regarding myelin repair, GABAergic signaling through GABA A Rs has been associated with remyelination after focal demyelination in the rat corpus callosum (Kalakh & Mouihate, 2019 ), as well as in the caudal cerebellar peduncle (Cisneros‐Mejorado et al, 2020 ). GABA B Rs have also been suggested as important modulators of myelination given that GABA B R antagonism increased OPC proliferation while decreasing their maturation and the production of myelin‐related proteins in the developing rat cingulum (Pudasaini et al, 2022 ). However, the role of oligodendroglial GABA B Rs in myelin regeneration remains to be investigated.…”

Neonatal Oxidative Stress Impairs Cortical Synapse Formation and GABA Homeostasis in Parvalbumin-Expressing Interneurons

“…In theory, the delay in synapse formation can diminish GABA transmission at early time points of brain development, which is of high relevance since GABA signaling plays a central role in regulating cortical development [ 75 ]. Accordingly, decreased GABA activity can impair white matter development and neuronal development [ 76 , 77 ] and might in our animals exposed to neonatal OS contribute or enhance OS-induced brain injury.…”

Cortical interneuron development is affected in leukodystrophy 4H

“…We investigated an alternative hypothesis, where the altered myelination is secondary to neuronal dysfunction. Cortical (parvalbumin) interneurons in the human brain are myelinated(35, 56), and myelination can be regulated by GABA receptor activity on oligodendrocytes(57). To study whether the decreased interneuron generation in 4H cortical cultures also affected myelination, a new co-culture protocol was developed.…”