Deletion of GABA‐B Receptor in Schwann Cells Regulates Remak Bundles and Small Nociceptive C‐fibers

Abstract

The mechanisms regulating the differentiation into non-myelinating Schwann cells is not completely understood. Recent evidence indicates that GABA-B receptors may regulate myelination and nociception in the peripheral nervous system. GABA-B receptor total knock-out mice exhibit morphological and molecular changes in peripheral myelin. The number of small myelinated fibers is higher and associated with altered pain sensitivity. Herein, we analyzed whether these changes may be produced by a specific deletion of GABA-B receptors in Schwann cells. The conditional mice (P0-GABA-B1(fl/fl)) show a morphological phenotype characterized by a peculiar increase in the number of small unmyelinated fibers and Remak bundles, including nociceptive C-fibers. The P0-GABA-B1(fl/fl) mice are hyperalgesic and allodynic. In these mice, the morphological and behavioral changes are associated with a downregulation of neuregulin 1 expression in nerves. Our findings suggest that the altered pain sensitivity derives from a Schwann cell-specific loss of GABA-B receptor functions, pointing to a role for GABA-B receptors in the regulation of Schwann cell maturation towards the non-myelinating phenotype.

Unwrapping the unappreciated: recent progress in Remak Schwann cell biology

“…Although axonal cues are certainly critical, several studies suggest some genes controlling SC fate decision may act cell-autonomously within SCs [13–15]. For example, SCs that have de-differentiated after injury can cell-autonomously upregulate Nrg1 to spur re-differentiation and remyelination [16].…”

“…During development, the gamma-aminobutyric acid type B1 receptor (GABBR1) localizes primarily, albeit not exclusively, in RSCs rather than myelinating SCs [17]. Faroni et al deleted Gabbr1 in embryonic SCs and observed increased numbers of small diameter axons, although the axons were properly ensheathed, which correlated with an increase in the number of Remak bundles relative to controls as well as a corresponding decrease in the number of larger diameter axons [15]. Myelin protein levels were significantly increased, and the myelin was slightly thicker in Gabbr1 mutant nerves, however these measurements did take into consideration axonal diameter.…”

“…As mentioned above, SC-specific loss of Gabbr1 resulted in increased numbers of unmyelinated c-fibers. This increase in Remak bundle density resulted in hypersensitivity to mechanical and thermal stimuli as well as altered locomotor coordination even in the absence of injury, although it is still somewhat unclear if this may be simply due to the changes in axon size distribution [15]. Additionally, loss of the LDL receptor related protein (LRP1), which is a potent regulator of SC migration and survival in vitro [38,39], resulted in slight hypomyelination and impaired RSC ensheathment in vivo , which then lead to mechanical allodynia in the absence of injury [40].…”

Nerve Regenerative Effects of GABA-B Ligands in a Model of Neuropathic Pain

“…Indeed, given the synergic effects on locomotors activities, the activation of mixed central and peripheral targets by those molecules should not be excluded. However, very recent findings supported the hypothesis that GABA-B receptors may also control the nonmyelinating Schwann cells committed to ensheath the nociceptive fibers, strengthening a GABA-B role in the regulation of Schwann cell fate and nociceptive pathways in the PNS [37, 38]. …”

“…Very recently, Schwann cells were shown to express different isoforms of GABA-B receptor, such as −1a, −1b, and −2, which can participate in the control of the Schwann cell development and in the myelination process [35, 36]. The peripheral GABA-B receptors in Schwann cells may be involved in the regulation of the sensory and nociceptive functions [37, 38]. …”