Developing oligodendrocytes express functional GABA_B receptors that stimulate cell proliferation and migration

Abstract

GABA B receptors (GABA B Rs) are involved in early events during neuronal development. The presence of GABA B Rs in developing oligodendrocytes has not been established. Using immunofluorescent co-localization, we have identified GA-BA B R proteins in O4 marker-positive oligodendrocyte precursor cells (OPCs) in 4-day-old mouse brain periventricular white matter. In culture, OPCs, differentiated oligodendrocytes (DOs) and type 2 astrocytes (ASTs) express both the GABA B1abcdf and GABA B2 subunits of the GABA B R. Using semiquantitative PCR analysis with GABA B R isoform-selective primers we found that the expression level of GABA B1abd was substantially higher in OPCs or ASTs than in DOs. In contrast, the GABA B2 isoform showed a similar level of expression in OPCs and DOs, and a significantly higher level in ASTs. This indicates that the expression of GABA B1 and GABA B2 subunits are under independent control during oligodendroglial development. Activation of GABA B Rs using the selective agonist baclofen demonstrated that these receptors are functionally active and negatively coupled to adenylyl cyclase. Manipulation of GABA B R activity had no effect on OPC migration in a conventional agarose drop assay, whereas baclofen significantly increased OPC migration in a more sensitive transwell microchamber-based assay. Exposure of cultured OPCs to baclofen increased their proliferation, providing evidence for a functional role of GABA B Rs in oligodendrocyte development. The presence of GABA B Rs in developing oligodendrocytes provides a new mechanism for neuronal-glial interactions during development and may offer a novel target for promoting remyelination following white matter injury.

Vigabatrin-induced CNS changes in juvenile rats: Induction, progression and recovery of myelin-related changes

“…While the mechanisms behind the vigabatrin-induced CNS changes are unknown the results presented suggest that the microvacuolation is caused by changes in the myelination process that in turns may be coupled to the developing oligodendrocyte. It has been demonstrated by Luyt et al (2007) that GABA receptors are involved in the early neuronal development and it is suggested that oligodendrocyte development may be influenced by GABA-induced Cl-fluxes (Lin & Bergles, 2004). Indeed, Lin and Bergles (2004) have demonstrated that activation of oligodendrocyte precursor cells appears to be influenced by GABA-induced Cl-fluxes and altered peripheral myelination has been demonstrated in mice lacking GABA(B) receptors (Magnaghi et al, 2008).…”

Electrophysiological properties of NG2 + cells: Matching physiological studies with gene expression profiles

“…Despite extensive characterization of GABA A R expression and GABAergic synaptic innervation of NG2 + cells, the question of whether GABA B receptors are also expressed by these cells was not addressed until relatively recently. Immunohistochemical analysis of NG2 + cells in hippocampal slices, in addition to RT-PCR and Western blot in the NG2 + cell-like CG-4 cell line, demonstrated that these cells express GABA B R1 and GABA B R2 (Luyt et al, 2007). Functional expression of these receptors has not been demonstrated electrophysiologically, but it was shown that the specific GABA B R agonist baclofen causes a reduction in cAMP levels and promotes the proliferation and migration of CG-4 cells, indicating that functional receptors are likely expressed (Luyt et al, 2007).…”

GABAA Receptor and Glycine Receptor Activation by Paracrine/Autocrine Release of Endogenous Agonists: More Than a Simple Communication Pathway

“…So far, there have been reports of GABA and/or GABA receptor expression by NG2+ cells [266], by oligodendrocyte progenitors [267][268][269] and by astrocytes [270], without any clear evidence for a physiological role.…”