GABA-B1 Receptor-Null Schwann Cells Exhibit Compromised In Vitro Myelination

Abstract

GABA-B receptors are important for Schwann cell (SC) commitment to a non-myelinating phenotype during development. However, the P0-GABA-B1 conditional knockout mice, lacking the GABA-B1 receptor specifically in SCs, also presented axon modifications, suggesting SC non-autonomous effects through the neuronal compartment. In this in vitro study, we evaluated whether the specific deletion of the GABA-B1 receptor in SCs may induce autonomous or non-autonomous cross-changes in sensory dorsal root ganglia (DRG) neurons. To this end, we performed an in vitro biomolecular and transcriptomic analysis of SC and DRG neuron primary cultures from P0-GABA-B1 mice. We found that cells from conditional P0-GABA-B1 mice exhibited proliferative, migratory and myelinating alterations. Moreover, we found transcriptomic changes in novel molecules that are involved in peripheral neuron-SC interaction.

Axonal GABAA stabilizes excitability in unmyelinated sensory axons secondary to NKCC1 activity

“…GABA A R subunit composition influences ligand sensitivity, channel kinetics, desensitization and spatial distribution within neurons (Mitchell et al, 2008). In adult DRG neurons, 3 is the most abundant GABA A R subunit (Ma et al, 1993;Faroni et al, 2019) and conditional deletion of GABA A R3 substantially reduced depolarizing GABA currents in DRG neuronal somata (Chen et al, 2014). GABA A R3 has also been identified immunohistochemically in the presynaptic terminals of primary afferent neurons in the spinal dorsal horn (Zeilhofer et al, 2012;Orefice et al, 2016).…”

Genomic and Non-genomic Action of Neurosteroids in the Peripheral Nervous System

“…In principle, the possibility of ALLO to interact with the metabotropic GABA-B receptor should not be completely excluded (Figure 2). To date, although a direct interaction of ALLO with GABA-B receptor was not clearly stated, several pieces of evidence highlighted a cross-regulation between GABA-A and GABA-B receptors in PNS (Magnaghi, 2007;Faroni et al, 2019). For instance, ALLO exerted a GABA-A mediated biphasic control of different GABA-B receptor subunits (Magnaghi et al, 2006a;Magnaghi, 2007).…”

“…In a neuropathic model of partial sciatic ligation, a 7-day administration of specific GABA-B ligands (i.e., baclofen and the antagonist CGP56433) strongly improved the biochemical, morphological and behavioral outcomes of sciatic nerve (Magnaghi et al, 2014). Furthermore, studies in transgenic mice with a conditional deletion of GABA-B1 receptor in PNS demonstrated that some important GABA-A subunits, expressed in SC and DRG neurons, were cross-regulated by GABA-B receptor (Faroni et al, 2019).…”

“…In the PNS, GABA-A receptor is widely distributed in nerves, neurons, and glial cells. SC express the α2 and 3, β1, 2, 3 and γ2 subunits ( Melcangi et al, 1999a ; Magnaghi et al, 2006a ), as well as the α4 and δ subunits, more characteristic of the extrasynaptic receptor ( Faroni et al, 2019 ). In addition, we found most of these subunits in the mouse DRG neuronal cultures, with predominant expression of the synaptic subunits α1, α2, β1, β3, γ2 ( Faroni et al, 2019 ).…”

“…SC express the α2 and 3, β1, 2, 3 and γ2 subunits ( Melcangi et al, 1999a ; Magnaghi et al, 2006a ), as well as the α4 and δ subunits, more characteristic of the extrasynaptic receptor ( Faroni et al, 2019 ). In addition, we found most of these subunits in the mouse DRG neuronal cultures, with predominant expression of the synaptic subunits α1, α2, β1, β3, γ2 ( Faroni et al, 2019 ). In general, in the PNS, the role of ALLO through GABA-A receptor has been widely characterized in the glial compartment, showing enhancement of SC proliferation, motility, differentiation and myelination ( Figure 2 ; see also the following chapter).…”